{"gene":"TIA1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1999,"finding":"TIA-1 acts downstream of eIF-2alpha phosphorylation to promote assembly of stress granules (SGs). A phosphomimetic eIF-2alpha mutant (S51D) induces SG assembly, a non-phosphorylatable mutant (S51A) prevents it, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation, placing TIA-1 downstream of eIF-2alpha in the pathway.","method":"Phosphomimetic/non-phosphorylatable eIF-2alpha mutant transfection, dominant-negative TIA-1 truncation mutant, fluorescence microscopy of SG assembly","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (phosphomimetic, non-phosphorylatable, dominant-negative), replicated in multiple labs","pmids":["10613902"],"is_preprint":false},{"year":2004,"finding":"Stress granule assembly is mediated by prion-like aggregation of TIA-1's glutamine-rich prion-related domain (PRD). The PRD is required for SG recruitment and exhibits concentration-dependent aggregation inhibited by HSP70; substitution of the PRD with the yeast prion domain SUP35-NM reconstitutes SG assembly. MEFs lacking TIA-1 show impaired SG formation with normal eIF2alpha phosphorylation, confirming TIA-1 acts downstream of eIF2alpha.","method":"Truncation/deletion mutants, PRD domain swap with yeast SUP35-NM, TIA-1 knockout MEFs, protease resistance assay, HSP70 co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution with heterologous prion domain, multiple orthogonal methods, KO MEF validation","pmids":["15371533"],"is_preprint":false},{"year":2000,"finding":"TIA-1 and PABP-I dynamically and continuously shuttle in and out of stress granules, as demonstrated by FRAP of GFP-tagged proteins in live cells. Drugs that stabilize polysomes (emetine) dissolve preformed SGs, while drugs that destabilize polysomes (puromycin) promote SG assembly, indicating SGs and polysomes exist in equilibrium.","method":"GFP-tagged TIA-1 live-cell imaging, FRAP, pharmacological manipulation (emetine, puromycin)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct FRAP quantification in live cells, multiple pharmacological controls, replicated concept across labs","pmids":["11121440"],"is_preprint":false},{"year":2000,"finding":"TIA-1 functions as a translational silencer of TNF-alpha. In TIA-1 knockout macrophages, TNF-alpha protein production is significantly increased without change in transcript levels or half-life, but with increased polysome association of TNF-alpha mRNA, indicating TIA-1 inhibits translation rather than mRNA stability.","method":"Homologous recombination knockout mice, polysome fractionation, LPS stimulation of macrophages, intracellular flow cytometry, ELISA","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with polysome fractionation and multiple readouts; independently confirmed in subsequent studies","pmids":["10921895"],"is_preprint":false},{"year":2000,"finding":"TIA-1 regulates alternative pre-mRNA splicing by binding U-rich sequences downstream of 5' splice sites and facilitating U1 snRNP recruitment, demonstrated for Drosophila msl-2 and human Fas pre-mRNAs.","method":"In vitro splicing assays, UV cross-linking, immunoprecipitation, overexpression in cultured cells, U1 snRNP recruitment assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro splicing reconstitution plus in vivo overexpression, replicated by multiple independent labs","pmids":["11106748"],"is_preprint":false},{"year":1996,"finding":"RNA binding specificity of TIA-1 is mediated primarily by RRM2, which selectively binds uridylate-rich sequences; replacing uridylates with cytidines abolishes binding. RRM3 can bind a broad population of cellular RNAs, while RRM1 does not bind RNA due to negatively charged residues in the RNP1 octamer.","method":"In vitro SELEX (selection/amplification from random RNA pools), filter binding assays, mutational analysis of individual RRM domains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro SELEX and mutagenesis with quantitative binding constants, single lab but rigorous biochemical dissection","pmids":["8576255"],"is_preprint":false},{"year":2002,"finding":"TIA-1 interacts directly with the U1 snRNP protein U1-C via its Q-rich domain (enhanced by RRM1), and RRM2+3 are required for pre-mRNA binding. This direct TIA-1/U1-C interaction facilitates recruitment of U1 snRNP to weak 5' splice sites.","method":"Co-precipitation assays with recombinant proteins, domain deletion analysis, in vitro U1 snRNP recruitment assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct protein-protein interaction mapped by co-precipitation with deletion mutants and functional validation in splicing assays","pmids":["12486009"],"is_preprint":false},{"year":2005,"finding":"TIA-1 promotes Fas exon 6 inclusion by enhancing U1 snRNP binding to the 5' splice site of intron 6, which in turn facilitates U2AF binding to the 3' splice site of intron 5 (exon definition). This opposes PTB-mediated exon skipping via an exonic splicing silencer.","method":"In vitro splicing assays, U1 snRNP and U2AF binding assays, PTB competition experiments, reporter minigene transfection","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of spliceosome assembly steps, multiple orthogonal approaches, independently validated","pmids":["16109372"],"is_preprint":false},{"year":1995,"finding":"Fas-activated serine/threonine kinase (FAST) is activated during Fas-mediated apoptosis and directly phosphorylates TIA-1. FAST dephosphorylation and concomitant activation precedes TIA-1 phosphorylation and DNA fragmentation, placing FAST upstream of TIA-1 in Fas apoptotic signaling.","method":"Kinase activation assays, phosphorylation of TIA-1 by immunoprecipitated FAST kinase in vitro, temporal analysis relative to DNA fragmentation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay demonstrating direct phosphorylation, temporal epistasis established","pmids":["7544399"],"is_preprint":false},{"year":2003,"finding":"TIA-1 binds the AU-rich element in the COX-2 mRNA 3'UTR and functions as a translational silencer of COX-2. TIA-1 null fibroblasts produce significantly more COX-2 protein without changes in transcription or mRNA turnover; colon cancer cells with COX-2 overexpression show defective TIA-1 binding.","method":"RNA binding studies, TIA-1 null fibroblasts (KO mice), COX-2 transcript stability assays, polysome analysis, in vitro RNA pulldown","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts confirming translational (not stability) regulation","pmids":["12885872"],"is_preprint":false},{"year":2005,"finding":"TIA-1 associates with a broad set of target mRNAs containing a U-rich bipartite motif (30-37 nt) predominantly in the 3'UTR, and represses their translation. The motif was identified by immunoprecipitation of TIA-1-RNA complexes followed by microarray analysis; RNAi knockdown of TIA-1 de-represses target mRNA translation.","method":"Immunoprecipitation of TIA-1-RNA complexes, microarray analysis, RT-PCR validation, biotinylated RNA pulldown/Western blot, RNAi knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation + microarray + RNAi with translational readout, multiple orthogonal methods in one study","pmids":["16227602"],"is_preprint":false},{"year":2006,"finding":"TIA-1 functions as a translational repressor of cytochrome c mRNA by binding its 3'UTR (proximal region), opposing the translational activator HuR. TIA-1 silencing dramatically increases cytochrome c translation; following ER stress, cytochrome c mRNA exits polysomes and translation declines.","method":"RNA-binding protein immunoprecipitation, siRNA knockdown, polysome fractionation, metabolic labeling of nascent cytochrome c protein","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with polysome fractionation, single lab with multiple readouts","pmids":["16581801"],"is_preprint":false},{"year":2006,"finding":"FAST kinase synergizes with TIA-1/TIAR to promote Fas exon 6 inclusion. Depletion of FAST K causes exon 6 skipping; FAST K overexpression effects are suppressed by TIA-1/TIAR depletion. In vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding, suggesting phosphorylation modulates protein-protein interactions at the spliceosome.","method":"siRNA depletion of FAST K, Fas minigene reporter assays, in vitro phosphorylation of TIA-1 by FAST K, U1 snRNP recruitment assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with functional splicing consequence, epistasis via knockdown, single lab","pmids":["17135269"],"is_preprint":false},{"year":2007,"finding":"TIA-1-induced translational silencing promotes mRNA decay via both the 5'-3' (DCP2-dependent) and 3'-5' (exosome Rrp46-dependent) decay pathways. TIA-1-mediated decay requires polysome disassembly (inhibited by cycloheximide/emetine but not puromycin); tethering TIA-1 to a reporter mRNA promotes its decay.","method":"siRNA knockdown of decay pathway components (DCP2, Rrp46), reporter mRNA tethering assay, polysome-stabilizing/destabilizing drugs, gene array analysis in TIA-1 KO macrophages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tethering assay plus siRNA epistasis of decay pathway components, single lab","pmids":["17711853"],"is_preprint":false},{"year":2008,"finding":"RSK2 directly interacts with the prion-related domain (PRD) of TIA-1 via its N-terminal kinase domain and co-localizes in stress granules in a codependent manner. Silencing RSK2 decreases cell survival under stress. Mitogen releases RSK2 from SGs for nuclear import, and nuclear accumulation of RSK2 depends on TIA-1.","method":"Co-immunoprecipitation of endogenous proteins, domain mapping with RSK2 N-terminal kinase domain, siRNA knockdown of RSK2, live-cell imaging of SG colocalization, nuclear fractionation","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, siRNA knockdown with survival phenotype, single lab","pmids":["18775331"],"is_preprint":false},{"year":2011,"finding":"TIA-1 and TIAR bind the 5' end of 5'TOP mRNAs upon amino acid starvation (requiring GCN2 activation and mTOR inactivation) and arrest translation at the initiation step, causing 5'TOP mRNA polysome release and accumulation in stress granules.","method":"RNA immunoprecipitation, polysome fractionation, siRNA knockdown of TIA-1/TIAR, GCN2 inhibition, mTOR inhibition/activation, stress granule microscopy","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, polysome fractionation, pathway epistasis (GCN2/mTOR), multiple orthogonal methods in one study","pmids":["21979918"],"is_preprint":false},{"year":2002,"finding":"TIA-1 (and TIAR) bind specifically to the 3' terminal stem-loop of West Nile virus minus-strand RNA via RRM2. WNV growth is less efficient in TIAR knockout cells but not in cells lacking other RNA virus susceptibility factors; reconstitution of TIAR restored WNV growth, suggesting TIA-1/TIAR facilitate flavivirus genome RNA replication.","method":"RNA affinity column purification, UV cross-linking/immunoprecipitation, recombinant protein competition gel-shift assays, TIAR KO cell lines, reconstitution experiments, virus growth assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding mapped to RRM2 with Kd values, KO and reconstitution with functional viral replication assay","pmids":["12414941"],"is_preprint":false},{"year":2014,"finding":"TIA-1 binds tick-borne encephalitis virus (TBEV) RNA in infected cells and is recruited to perinuclear sites of viral replication, depleting SGs. TIA-1 inhibits TBEV at the level of first-round viral translation, as TIA-1 KO fibroblasts show increased luciferase activity from a TBEV replicon at early time points.","method":"RNA immunoprecipitation in TBEV-infected cells, siRNA knockdown, TIA-1 KO MEFs, TBEV-luciferase replicon assay, immunofluorescence microscopy","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells, replicon functional assay, RIP, multiple orthogonal approaches, single lab","pmids":["24696465"],"is_preprint":false},{"year":2014,"finding":"TIA-1 NMR solution structure (RRM2-RRM3) reveals RRM2 adopts a canonical RRM fold while RRM3 is preceded by a non-canonical helix α0. All three RRMs are largely independent in the absence of RNA but adopt a compact arrangement upon RNA binding. RRM2,3 binds pyrimidine-rich RNA with nanomolar affinity; RRM1 has little intrinsic RNA binding affinity.","method":"NMR spectroscopy (solution structure of RRM2-RRM3), SAXS, isothermal titration calorimetry (ITC), RNA binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination with SAXS and ITC functional validation, single lab but multiple orthogonal biophysical methods","pmids":["24682828"],"is_preprint":false},{"year":2016,"finding":"TIA-1 oxidation by reactive oxygen species (H2O2) inhibits stress granule assembly. When cells face concurrent ER stress and oxidative stress, ROS-oxidized TIA1 cannot form SGs, leading to enhanced apoptosis. This demonstrates that TIA1's SG-nucleating activity is redox-regulated.","method":"H2O2 treatment combined with ER stress (tunicamycin), SG formation assays by immunofluorescence, TIA1 oxidation biochemical analysis, cell viability/apoptosis assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct oxidative modification of TIA1 with functional SG assembly and apoptosis readouts, single lab","pmids":["26738979"],"is_preprint":false},{"year":2016,"finding":"Tau interacts with TIA1 in brain tissue, and tau regulates the distribution of TIA1 and accelerates stress granule formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while TIA1 overexpression induces tau misfolding and neurodegeneration.","method":"Co-immunoprecipitation from brain tissue, TIA1 interactome analysis (MS), TIA1 KO/KD in hippocampal neurons, tau misfolding assays, pharmacological SG inhibition","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from brain tissue, KO/KD with cellular toxicity phenotype, single lab with multiple methods","pmids":["27160897"],"is_preprint":false},{"year":2017,"finding":"ALS/FTD-associated mutations in the TIA1 low-complexity domain (LCD), including P362L, increase TIA1's propensity to undergo phase transition, delay SG disassembly, promote accumulation of non-dynamic SGs harboring TDP-43, and render TDP-43 less mobile and insoluble.","method":"Patient-derived genetic analysis, phase separation assays in vitro, live-cell SG dynamics (FRAP), TDP-43 mobility and solubility assays, postmortem neuropathology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro phase separation, FRAP in live cells, multiple patient mutations, neuropathology correlation; replicated by subsequent structural studies","pmids":["28817800"],"is_preprint":false},{"year":2018,"finding":"Recombinant TIA-1 undergoes rapid multimerization and phase separation in the presence of divalent zinc (Zn2+), reversible by the zinc chelator TPEN. In arsenite-stressed cells, Zn2+ is released before SG formation, and TPEN inhibits formation and maintenance of TIA-1-positive SGs, identifying Zn2+ as a physiological second messenger for TIA-1 multimerization.","method":"Recombinant TIA-1 phase separation assay with ZnCl2, TPEN chelation rescue, Zn2+ release measurement in arsenite-treated cells, immunofluorescence SG assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with recombinant protein and functional in-cell validation, single lab","pmids":["29298433"],"is_preprint":false},{"year":2018,"finding":"Double knockout of TIA1 and TIAL1 increases target mRNA abundance proportional to binding site number and causes accumulation of aberrantly spliced mRNAs subject to NMD. Loss of PRKRA by mis-splicing activates PKR (EIF2AK2) and triggers spontaneous SG formation; ectopic PRKRA cDNA or EIF2AK2 knockout in DKO cells rescues this phenotype.","method":"CRISPR double KO of TIA1/TIAL1, PAR-CLIP for target site mapping, RNA-seq for splicing/abundance, ectopic PRKRA cDNA rescue, EIF2AK2 KO epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — double KO with PAR-CLIP target mapping, epistasis rescue with cDNA and second KO, multiple orthogonal methods","pmids":["29429924"],"is_preprint":false},{"year":2005,"finding":"TIA-1 and TIAR continuously shuttle between nucleus and cytoplasm in a transcription-dependent manner. RRM2 and the first half of the auxiliary region mediate nuclear accumulation; RRM3 mediates nuclear export. Both RRMs contribute to localization through their RNA-binding capacity. Nuclear export is Ran-GTP-independent and CRM1-independent.","method":"Domain truncation/mutation analysis, leptomycin B (CRM1 inhibitor) treatment, Ran-GTP depletion, transcription inhibitors, fluorescence microscopy of GFP-tagged constructs","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutants with functional localization readouts and pathway inhibitors, single lab","pmids":["16278295"],"is_preprint":false},{"year":2007,"finding":"TIA-1 binds to AU-rich sequences in COL2A1 intron 2, modulates alternative splicing of COL2A1 exon 2, and also interacts with the equivalent single-stranded DNA sequence in vivo (confirmed by chromatin immunoprecipitation), suggesting a dual role at both transcription and pre-mRNA splicing levels.","method":"Minigene splicing assays, RNP immunoprecipitation for pre-mRNA binding, chromatin immunoprecipitation (ChIP) with RNase step, competition assays for DNA vs RNA binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNP-IP and ChIP with functional splicing readout, single lab with multiple approaches","pmids":["17580305"],"is_preprint":false},{"year":2008,"finding":"TIA-1 and TIAR binding sites in the West Nile virus 3' minus-strand stem-loop RNA were mapped to short AU sequences (UAAUU) in internal loops. Infectious clone RNAs with deleted/substituted binding sites showed decreased TIAR/TIA-1 binding efficiency correlated with decreased intracellular genomic RNA levels and virus production, implicating TIA-1/TIAR binding in asymmetric amplification of genomic RNA from the minus-strand template.","method":"Infectious clone RNA mutagenesis, in vitro protein binding assays, plaque assays, intracellular RNA quantification by qRT-PCR","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis of viral RNA binding sites with functional viral replication readout, single lab","pmids":["18768985"],"is_preprint":false},{"year":2009,"finding":"Sam68 is recruited to stress granules under oxidative stress through direct complex formation with TIA-1. Domains aa269-321 and the KH domain of Sam68 are essential for SG recruitment, but Sam68 knockdown does not impair SG assembly.","method":"Co-immunoprecipitation of Sam68 and TIA-1, domain deletion mapping, siRNA knockdown of Sam68, immunofluorescence of SG markers under oxidative stress","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with domain mapping, single lab, no reciprocal IP with TIA-1","pmids":["19615357"],"is_preprint":false},{"year":2010,"finding":"TIA1 prevents skipping of SMN2 exon 7 in a novel context where intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. Any single RRM combined with the Q domain is sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. TIA1 counteracts the inhibitory effect of PTB on SMN exon 7 splicing.","method":"In vivo splicing assays with TIA1/TIAR expression, domain deletion/chimeric protein analysis, co-expression with PTB, RT-PCR of endogenous SMN2 exon 7 splicing","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo splicing assays with systematic domain dissection and epistasis with PTB, single lab","pmids":["21189287"],"is_preprint":false},{"year":2011,"finding":"TDP-43 differentially regulates key SG components: controlled aggregation of TIA-1 is disrupted in the absence of TDP-43, resulting in slowed SG formation. TDP-43 also regulates G3BP mRNA levels. The disease mutation TDP-43(R361S) is a loss-of-function mutation for SG formation and alters TIA-1 and G3BP levels.","method":"TDP-43 siRNA knockdown, oxidative stress/heat shock/thapsigargin-induced SG assays, immunofluorescence, Western blot for TIA-1 and G3BP, TDP-43 mutant expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with functional SG readout and mutation analysis, single lab","pmids":["21257637"],"is_preprint":false},{"year":2013,"finding":"Welander distal myopathy (WDM) is caused by the E384K mutation in TIA1's Q-rich domain. Mutant TIA1 causes increased SG abundance and slower FRAP kinetics in HeLa cells, consistent with altered SG dynamics. The E384K mutation is in the domain that interacts with U1-C splicing factor, and WDM patients have increased SMN2 exon 7 skipping.","method":"Genetic sequencing/linkage analysis, Western blot and immunofluorescence of WDM muscle biopsies, high-content SG quantification in HeLa cells, FRAP, RT-PCR of SMN2 splicing","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and SG quantification with identified mutation, multiple methods but single patient cohort study","pmids":["23401021"],"is_preprint":false},{"year":2014,"finding":"In yeast, Tia1/Pub1 forms a prion and cooperates with Sup35/eRF3 to establish a two-protein self-propagating state along tubulin cytoskeleton. A tubulin-associated complex containing Pub1 and Sup35 oligomers (plus TUB1 mRNA and translation machinery) depends on prion domains; PUB1 disruption leads to cytoskeletal defects.","method":"Yeast prion assays, fluorescence microscopy of line structures along tubulin, genetic disruption of PUB1, co-purification of Pub1/Sup35/TUB1 mRNA complex","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast prion assay with genetic and biochemical validation; ortholog study in S. cerevisiae consistent with mammalian TIA1 prion function","pmids":["24981173"],"is_preprint":false},{"year":2014,"finding":"TIA-1 RRM3 binds both C-rich and U-rich sequences with micromolar affinity, and in the context of full-length TIA-1, RRM3 significantly enhances binding to C-rich RNA (including 5'TOP sequences), as demonstrated by STD-NMR and biotinylated RNA pulldown.","method":"STD-NMR, surface plasmon resonance (SPR), biotinylated RNA pulldown/Western blot with full-length TIA-1 and isolated domains","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR and SPR biophysical characterization of RNA binding, single lab with multiple methods","pmids":["24824036"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of TIA-1 RRM2 in complex with DNA at 2.3 Å resolution provides the first atomic-resolution structure of any TIA protein RRM with oligonucleotide. SAXS shows TIA-1 RRM23 adopts a compact structure upon complex formation with target RNA or DNA; both RRMs engage the 10-nt target sequence.","method":"X-ray crystallography (2.3 Å), SAXS, in vitro binding assays, site-directed mutagenesis (Lys274)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination with SAXS and functional binding validation, single lab but high-resolution structural evidence","pmids":["28184449"],"is_preprint":false},{"year":2021,"finding":"TIA1 interaction with RNA and the presence of TIA1 protein together are sufficient to drive phase separation of tau at physiological concentrations without crowding agents. Phase separation of tau with TIA1 generates abundant tau oligomers that are significantly more toxic than tau aggregates formed with RNA alone, identifying a mechanism for generating toxic tau species.","method":"In vitro phase separation assay with recombinant proteins and RNA, tau oligomer toxicity assays, comparison with other RBPs (G3BP1) and crowding agents (PEG)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — biochemical reconstitution in vitro with multiple conditions, toxicity readout, single lab","pmids":["33619090"],"is_preprint":false},{"year":2021,"finding":"Tandem RNA binding sites (not single sites) are required to enhance TIA-1 phase separation. Single-stranded RNA and DNA with tandem binding sites efficiently promote both liquid-liquid phase separation and amyloid-like fibril formation of full-length TIA-1 in vitro; this is finely tuned by protein:binding site stoichiometry.","method":"In vitro phase separation assays with designed and native RNA/DNA sequences, fibril formation assays, SAXS for conformational analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic variation of binding site number/stoichiometry, single lab","pmids":["33621982"],"is_preprint":false},{"year":2022,"finding":"NMR analysis and molecular dynamics simulations reveal that TIA1 PLD dynamic structure is determined by physicochemical properties in 5-residue units. ALS mutations P362L and A381T enhance self-assembly by inducing β-sheet interactions and highly condensed assemblies (promoting irreversible amyloid fibrillization), while WDM mutation E384K attenuates sticky properties.","method":"NMR analysis, molecular dynamics simulations, 3D electron crystallography, biochemical aggregation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR + electron crystallography + MD simulations with biochemical validation, multiple disease mutations characterized","pmids":["36112647"],"is_preprint":false},{"year":2017,"finding":"TIA1 (Tia1) controls translational silencing of p53 mRNA and its localization to stress granules in activated B lymphocytes. Upon DNA damage, p53 mRNA is released from TIA1-containing stress granules and associates with polyribosomes for CAP-independent translation. Tia1 dissociation from mRNA targets is part of the ATM-dependent DNA damage response.","method":"RIP (TIA1), polyribosome fractionation, stress granule isolation, RNA granule localization imaging, knockout/knockdown analysis in primary B cells, global translation profiling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP with polysome fractionation and granule localization, functional rescue in primary cells, single lab","pmids":["28904350"],"is_preprint":false},{"year":2014,"finding":"TIA1 interacts with annexin A7 (ANXA7), and this interaction regulates TIA1 phosphorylation. Treatment with ABO (ANXA7 inhibitor) promotes TIA1-ANXA7 interaction and inhibits TIA1 phosphorylation in HUVECs, leading to increased expression of ATG13 (pro-autophagy) via FLJ11812 processing.","method":"Yeast two-hybrid screening, co-immunoprecipitation, ABO treatment, Western blot for phospho-TIA1, autophagy marker quantification","journal":"The international journal of biochemistry & cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid and Co-IP with pharmacological intervention, single lab, indirect phosphorylation readout","pmids":["25461769"],"is_preprint":false},{"year":2017,"finding":"TIA1 N-terminal region coordinates with Pcbp1 and RBM39 to activate 3' splice site of protein 4.1R exon 16. TIA1 and Pcbp1 bind a UUUUCCCCCC motif between branch point and 3' splice site; together with RBM39, they promote U2 snRNP recruitment and spliceosome A complex formation via RBM39-U2AF65-SF3b155 interactions.","method":"In vitro splicing assays, RNA binding/UV cross-linking, RNAi knockdown, co-immunoprecipitation of RBM39/TIA1/Pcbp1 complex, U2 snRNP recruitment assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical reconstitution with co-IP of multi-protein complex and functional splicing assays, single lab","pmids":["28193846"],"is_preprint":false}],"current_model":"TIA-1 is an RNA-binding protein with three RRMs (RRM2 mediates U-rich RNA binding, RRM3 augments binding to C-rich sequences, RRM1 enhances U1-C interaction) and a C-terminal prion-like Q-rich domain that, upon cellular stress, drives liquid-liquid phase separation and aggregation downstream of eIF2alpha phosphorylation to nucleate stress granules where it sequesters and translationally silences target mRNAs; it also promotes inclusion of weak 5' splice sites by directly binding U-rich intronic sequences and recruiting U1 snRNP through a direct RRM1/Q-domain interaction with U1-C; TIA-1 activity is regulated by FAST kinase phosphorylation, Zn2+-induced multimerization, and ROS-mediated oxidation, and disease-associated mutations in its low-complexity domain pathologically enhance phase transition and delay SG disassembly, linking TIA-1 to ALS/FTD and tauopathy."},"narrative":{"mechanistic_narrative":"TIA-1 is a multidomain RNA-binding protein that couples mRNA recognition to two cellular functions—translational silencing within stress granules and regulation of alternative pre-mRNA splicing [PMID:10613902, PMID:11106748]. RNA recognition is mediated by tandem RRMs: RRM2 selectively binds uridylate-rich sequences while RRM1 lacks intrinsic RNA-binding capacity, and RRM3 augments binding to C-rich and 5'TOP sequences [PMID:8576255, PMID:24824036], with crystallographic and NMR/SAXS data showing RRM2-RRM3 collapse into a compact arrangement upon engaging a 10-nucleotide pyrimidine target [PMID:24682828, PMID:28184449]. Through these domains TIA-1 binds U-rich bipartite motifs predominantly in 3'UTRs and represses translation of target mRNAs including TNF-alpha, COX-2, cytochrome c, and p53 without altering transcript levels [PMID:10921895, PMID:12885872, PMID:16227602, PMID:16581801, PMID:28904350], and this silencing can be coupled to mRNA decay via both 5'-3' and 3'-5' pathways [PMID:17711853]. Upon eIF2alpha phosphorylation and polysome disassembly, TIA-1 nucleates stress granules through prion-like aggregation of its C-terminal glutamine-rich domain, into and out of which it dynamically shuttles [PMID:10613902, PMID:15371533, PMID:11121440]; this self-assembly is promoted by tandem RNA binding sites and by Zn2+-induced multimerization, and is inhibited by ROS-mediated oxidation [PMID:29298433, PMID:26738979, PMID:33621982]. In the nucleus TIA-1 promotes inclusion of weak 5' splice sites by binding U-rich intronic sequences and recruiting U1 snRNP through a direct interaction between its Q-rich domain and U1-C, facilitating exon definition (e.g. Fas exon 6, SMN2 exon 7) and opposing PTB-mediated skipping [PMID:11106748, PMID:12486009, PMID:16109372, PMID:21189287]. TIA-1 activity is modulated by FAST kinase phosphorylation, which enhances U1 snRNP recruitment at the spliceosome [PMID:7544399, PMID:17135269]. Disease-associated mutations in the low-complexity/Q-rich domain pathologically alter phase behavior: ALS/FTD mutations (P362L, A381T) enhance beta-sheet-driven self-assembly and delay disassembly of TDP-43-containing stress granules, whereas the Welander distal myopathy mutation E384K alters SG dynamics and SMN2 splicing [PMID:28817800, PMID:36112647, PMID:23401021]. TIA-1 also drives toxic tau oligomer formation and accelerates tau misfolding, linking it to tauopathy [PMID:27160897, PMID:33619090].","teleology":[{"year":1995,"claim":"Established that TIA-1 is a substrate of an apoptotic signaling kinase, providing the first link between TIA-1 and regulated post-transcriptional control during Fas-mediated cell death.","evidence":"in vitro phosphorylation of TIA-1 by immunoprecipitated FAST kinase with temporal epistasis to DNA fragmentation","pmids":["7544399"],"confidence":"High","gaps":["phosphorylation sites not mapped","functional consequence of phosphorylation not defined at this stage"]},{"year":1996,"claim":"Resolved which domains confer RNA specificity, showing RRM2 drives U-rich binding while RRM1 is non-binding—defining the modular logic of TIA-1 recognition.","evidence":"in vitro SELEX, filter binding, and per-RRM mutational analysis","pmids":["8576255"],"confidence":"High","gaps":["structural basis of specificity not yet resolved","in vivo target spectrum unknown"]},{"year":1999,"claim":"Placed TIA-1 genetically downstream of eIF2alpha phosphorylation in stress granule assembly, establishing it as an effector of the translational stress response.","evidence":"phosphomimetic/non-phosphorylatable eIF2alpha mutants and dominant-negative TIA-1 truncation with SG microscopy","pmids":["10613902"],"confidence":"High","gaps":["domain responsible for SG nucleation not identified here","molecular nature of aggregation undefined"]},{"year":2000,"claim":"Defined TIA-1's two parallel functions—translational silencing of specific mRNAs and splice-site selection—answering what TIA-1 actually does to its bound RNAs.","evidence":"TIA-1 knockout macrophages with polysome fractionation (TNF-alpha); in vitro splicing and U1 recruitment assays (Fas, msl-2); FRAP of GFP-TIA-1 in live cells","pmids":["10921895","11106748","11121440"],"confidence":"High","gaps":["how silencing and splicing functions are partitioned between compartments unclear","global target set not yet defined"]},{"year":2002,"claim":"Identified the direct protein-protein contact—Q-domain/U1-C—through which TIA-1 recruits U1 snRNP, providing the mechanism for its splicing-enhancer activity.","evidence":"co-precipitation of recombinant proteins with domain deletions and in vitro U1 recruitment","pmids":["12486009"],"confidence":"High","gaps":["structural detail of the interaction absent","regulation of the contact unknown at this stage"]},{"year":2002,"claim":"Extended TIA-1 RNA recognition to viral templates, showing RRM2-mediated binding to flavivirus minus-strand RNA promotes genome replication.","evidence":"RNA affinity purification, gel-shift, TIAR KO and reconstitution with WNV growth assays","pmids":["12414941"],"confidence":"Medium","gaps":["mechanism of replication enhancement not resolved","single virus family tested"]},{"year":2004,"claim":"Pinned SG assembly on prion-like aggregation of the Q-rich PRD, explaining how TIA-1 physically nucleates granules.","evidence":"PRD deletion, swap with yeast SUP35-NM, protease resistance, HSP70 Co-IP, and TIA-1 KO MEFs","pmids":["15371533"],"confidence":"High","gaps":["biophysical nature of aggregation (LLPS vs amyloid) not distinguished","regulation of aggregation undefined"]},{"year":2003,"claim":"Generalized TIA-1 translational silencing to additional ARE-containing transcripts and a global target motif, with COX-2 implicating TIA-1 loss in cancer.","evidence":"TIA-1 null fibroblasts, RNA pulldown, polysome analysis (COX-2); TIA-1-RNA IP plus microarray and RNAi de-repression (global U-rich motif)","pmids":["12885872","16227602"],"confidence":"High","gaps":["mechanism of translational block not defined at codon/initiation level","how silencing relates to SG sequestration unclear"]},{"year":2005,"claim":"Connected splicing enhancement to exon definition and characterized nucleocytoplasmic shuttling, integrating TIA-1's nuclear and cytoplasmic behaviors.","evidence":"in vitro reconstitution of U1/U2AF cross-talk at Fas exon 6; domain-mutant localization with CRM1/Ran-independence","pmids":["16109372","16278295"],"confidence":"High","gaps":["export receptor for TIA-1 unidentified","signals coupling localization to function unknown"]},{"year":2006,"claim":"Showed FAST kinase phosphorylation tunes TIA-1 splicing activity at the protein-interaction level rather than RNA binding, linking the 1995 kinase substrate finding to function.","evidence":"FAST K siRNA, Fas minigene assays, in vitro phosphorylation with U1 recruitment readout; cytochrome c RIP and polysome work opposing HuR","pmids":["17135269","16581801"],"confidence":"Medium","gaps":["phosphosites still unmapped","mechanism by which phosphorylation enhances U1 recruitment unresolved"]},{"year":2007,"claim":"Showed silencing is mechanistically coupled to mRNA decay and that TIA-1 can engage DNA, broadening its regulatory range.","evidence":"tethering assays with DCP2/Rrp46 siRNA epistasis (decay); ChIP and RNP-IP at COL2A1 (DNA/RNA dual binding)","pmids":["17711853","17580305"],"confidence":"Medium","gaps":["whether decay is direct or secondary to polysome disassembly unclear","physiological significance of DNA binding undefined"]},{"year":2008,"claim":"Identified RSK2 as a PRD-interacting kinase partner co-regulated with TIA-1 in stress granules, linking SG dynamics to cell survival signaling.","evidence":"reciprocal Co-IP, domain mapping, RSK2 siRNA survival phenotype, nuclear fractionation","pmids":["18775331"],"confidence":"Medium","gaps":["whether RSK2 phosphorylates TIA-1 not established","single-lab finding"]},{"year":2011,"claim":"Tied TIA-1 silencing to nutrient sensing, showing it arrests 5'TOP mRNA translation downstream of GCN2/mTOR, and revealed TDP-43 dependence of TIA-1 aggregation.","evidence":"RIP, polysome fractionation, GCN2/mTOR perturbation (5'TOP); TDP-43 knockdown with SG dynamics and mutant analysis","pmids":["21979918","21257637"],"confidence":"High","gaps":["how 5'TOP recognition is achieved structurally unclear","TDP-43/TIA-1 interplay mechanism undefined"]},{"year":2014,"claim":"Provided atomic and biophysical structure of the RNA-engaged RRM module and refined RRM3 specificity, explaining how TIA-1 reads pyrimidine-rich targets.","evidence":"NMR solution structure of RRM2-RRM3, SAXS, ITC; STD-NMR/SPR for RRM3 C-rich binding","pmids":["24682828","24824036"],"confidence":"High","gaps":["RRM1 contribution structurally unresolved","PRD structure not addressed"]},{"year":2014,"claim":"Demonstrated conserved prion behavior of the TIA-1 ortholog and added a flavivirus-restriction/replication role, situating phase behavior in deep evolutionary and antiviral contexts.","evidence":"yeast Pub1 prion assays with Sup35 cooperation; TBEV replicon and KO MEF assays; WNV binding-site mutagenesis with viral RNA quantitation","pmids":["24981173","24696465","18768985"],"confidence":"Medium","gaps":["whether viral roles are restriction or pro-replication is context-dependent and unresolved","ortholog prion mechanism not directly demonstrated for human TIA-1"]},{"year":2016,"claim":"Established redox control of SG nucleation and identified tau as a brain interactor whose toxicity depends on TIA-1, opening the neurodegeneration axis.","evidence":"H2O2 oxidation with SG/apoptosis assays; brain Co-IP, TIA-1 KO/KD with tau misfolding readouts","pmids":["26738979","27160897"],"confidence":"Medium","gaps":["oxidized residues not mapped","direct vs indirect tau interaction not fully resolved"]},{"year":2017,"claim":"Defined disease mutation mechanism (LCD mutations enhance phase transition and trap TDP-43) and added p53 silencing plus multi-protein splicing roles, unifying biophysics, splicing, and disease.","evidence":"patient mutations with in vitro LLPS, FRAP, TDP-43 solubility and neuropathology (P362L); p53 RIP/polysome in B cells; RBM39/Pcbp1/TIA-1 splicing complex reconstitution","pmids":["28817800","28904350","28193846"],"confidence":"High","gaps":["link between altered SG dynamics and neuronal death not fully causal","in vivo consequences of mutations not modeled"]},{"year":2018,"claim":"Identified Zn2+ as a physiological multimerization trigger and used double knockout to reveal that TIA-1/TIAL1 loss drives mis-splicing-induced PKR activation and spontaneous SGs.","evidence":"recombinant LLPS with ZnCl2/TPEN and in-cell Zn2+ release; CRISPR DKO with PAR-CLIP, RNA-seq, PRKRA/EIF2AK2 epistasis rescue","pmids":["29298433","29429924"],"confidence":"High","gaps":["zinc-binding site on TIA-1 not localized","physiological relevance of the PKR feedback loop in vivo unclear"]},{"year":2021,"claim":"Showed tandem RNA binding sites tune TIA-1 phase separation/fibrillization and that TIA-1 directly drives toxic tau oligomer formation, defining how RNA stoichiometry and tau converge on pathological assemblies.","evidence":"in vitro LLPS/fibril assays with designed tandem-site RNA/DNA and SAXS; reconstituted tau-TIA-1 phase separation with oligomer toxicity assays","pmids":["33621982","33619090"],"confidence":"Medium","gaps":["in-cell relevance of tandem-site tuning not shown","structure of toxic tau-TIA-1 species undefined"]},{"year":2022,"claim":"Resolved at residue resolution how PLD physicochemistry governs assembly and how ALS vs WDM mutations act oppositely—ALS mutations enhancing amyloid, WDM mutation attenuating stickiness.","evidence":"NMR, molecular dynamics, 3D electron crystallography, and aggregation assays of PLD with multiple disease mutations","pmids":["36112647"],"confidence":"High","gaps":["link to full-length cellular phase behavior partly indirect","therapeutic targeting of PLD not addressed"]},{"year":null,"claim":"How TIA-1's distinct activities—splice-site selection, translational silencing, and stress-granule/aggregate formation—are coordinated, compartment-resolved, and pharmacologically targetable in disease remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no integrated model coupling RNA binding stoichiometry to in-cell phase behavior","phosphorylation/oxidation/zinc inputs not mapped to defined residues in vivo","no demonstration that modulating TIA-1 phase transition rescues neurodegeneration in animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,10,16,18,32,33]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[3,9,10,11,37]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7,28,39]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[25,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,39]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,24]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,7,10,13,28]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,19,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,9,11,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,30,36,20]}],"complexes":["stress granule","U1 snRNP-associated spliceosomal complex"],"partners":["U1-C","TIAL1","TDP-43","RSK2","SAM68","RBM39","PCBP1","MAPT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31483","full_name":"Cytotoxic granule associated RNA binding protein TIA1","aliases":["Nucleolysin TIA-1 isoform p40","RNA-binding protein TIA-1","T-cell-restricted intracellular antigen-1","TIA-1","p40-TIA-1"],"length_aa":386,"mass_kda":43.0,"function":"RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences (PubMed:11106748, PubMed:12486009, PubMed:17488725, PubMed:8576255). Binds to U-rich sequences immediately downstream from a 5' splice sites in a uridine-rich small nuclear ribonucleoprotein (U snRNP)-dependent fashion, thereby modulating alternative pre-RNA splicing (PubMed:11106748, PubMed:8576255). Preferably binds to the U-rich IAS1 sequence in a U1 snRNP-dependent manner; this binding is optimal if a 5' splice site is adjacent to IAS1 (By similarity). Activates the use of heterologous 5' splice sites; the activation depends on the intron sequence downstream from the 5' splice site, with a preference for a downstream U-rich sequence (PubMed:11106748). By interacting with SNRPC/U1-C, promotes recruitment and binding of spliceosomal U1 snRNP to 5' splice sites followed by U-rich sequences, thereby facilitating atypical 5' splice site recognition by U1 snRNP (PubMed:11106748, PubMed:12486009, PubMed:17488725). Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIAR mRNA (By similarity). Acts as a modulator of alternative splicing for the apoptotic FAS receptor, thereby promoting apoptosis (PubMed:11106748, PubMed:17488725, PubMed:1934064). Binds to the 5' splice site region of FAS intron 5 to promote accumulation of transcripts that include exon 6 at the expense of transcripts in which exon 6 is skipped, thereby leading to the transcription of a membrane-bound apoptotic FAS receptor, which promotes apoptosis (PubMed:11106748, PubMed:17488725, PubMed:1934064). Binds to a conserved AU-rich cis element in COL2A1 intron 2 and modulates alternative splicing of COL2A1 exon 2 (PubMed:17580305). Also binds to the equivalent AT-rich element in COL2A1 genomic DNA, and may thereby be involved in the regulation of transcription (PubMed:17580305). Binds specifically to a polypyrimidine-rich controlling element (PCE) located between the weak 5' splice site and the intronic splicing silencer of CFTR mRNA to promote exon 9 inclusion, thereby antagonizing PTB1 and its role in exon skipping of CFTR exon 9 (PubMed:14966131). Involved in the repression of mRNA translation by binding to AU-rich elements (AREs) located in mRNA 3' untranslated regions (3' UTRs), including target ARE-bearing mRNAs encoding TNF and PTGS2 (By similarity). Also participates in the cellular response to environmental stress, by acting downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SGs), leading to stress-induced translational arrest (PubMed:10613902). Formation and recruitment to SGs is regulated by Zn(2+) (By similarity). Possesses nucleolytic activity against cytotoxic lymphocyte target cells (PubMed:1934064) Displays enhanced splicing regulatory activity compared with TIA isoform Long","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/P31483/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TIA1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000116001","cell_line_id":"CID002025","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":4.0},{"gene":"STT3A","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"KRTCAP2","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"OSTC","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"STT3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID002025","total_profiled":1310},"omim":[{"mim_id":"621078","title":"MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES; MFM13","url":"https://www.omim.org/entry/621078"},{"mim_id":"619133","title":"AMYOTROPHIC LATERAL SCLEROSIS 26 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS26","url":"https://www.omim.org/entry/619133"},{"mim_id":"610747","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 4A; SAMD4A","url":"https://www.omim.org/entry/610747"},{"mim_id":"606965","title":"FAS-ACTIVATED SERINE/THREONINE KINASE; FASTK","url":"https://www.omim.org/entry/606965"},{"mim_id":"604454","title":"WELANDER DISTAL MYOPATHY; WDM","url":"https://www.omim.org/entry/604454"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TIA1"},"hgnc":{"alias_symbol":["TIA-1"],"prev_symbol":[]},"alphafold":{"accession":"P31483","domains":[{"cath_id":"3.30.70.330","chopping":"7-79","consensus_level":"high","plddt":89.2821,"start":7,"end":79},{"cath_id":"3.30.70.330","chopping":"105-180","consensus_level":"high","plddt":90.9263,"start":105,"end":180},{"cath_id":"3.30.70.330","chopping":"201-287","consensus_level":"high","plddt":92.2744,"start":201,"end":287}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31483","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31483-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31483-F1-predicted_aligned_error_v6.png","plddt_mean":73.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TIA1","jax_strain_url":"https://www.jax.org/strain/search?query=TIA1"},"sequence":{"accession":"P31483","fasta_url":"https://rest.uniprot.org/uniprotkb/P31483.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31483/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31483"}},"corpus_meta":[{"pmid":"10613902","id":"PMC_10613902","title":"RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10613902","citation_count":1074,"is_preprint":false},{"pmid":"15371533","id":"PMC_15371533","title":"Stress granule assembly is mediated by prion-like aggregation of TIA-1.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15371533","citation_count":832,"is_preprint":false},{"pmid":"11121440","id":"PMC_11121440","title":"Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11121440","citation_count":670,"is_preprint":false},{"pmid":"28817800","id":"PMC_28817800","title":"TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.","date":"2017","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/28817800","citation_count":507,"is_preprint":false},{"pmid":"10921895","id":"PMC_10921895","title":"TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10921895","citation_count":437,"is_preprint":false},{"pmid":"21257637","id":"PMC_21257637","title":"TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21257637","citation_count":337,"is_preprint":false},{"pmid":"16109372","id":"PMC_16109372","title":"Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16109372","citation_count":291,"is_preprint":false},{"pmid":"27160897","id":"PMC_27160897","title":"Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27160897","citation_count":275,"is_preprint":false},{"pmid":"17502609","id":"PMC_17502609","title":"Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17502609","citation_count":255,"is_preprint":false},{"pmid":"11106748","id":"PMC_11106748","title":"The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11106748","citation_count":253,"is_preprint":false},{"pmid":"12380690","id":"PMC_12380690","title":"Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation.","date":"2002","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/12380690","citation_count":217,"is_preprint":false},{"pmid":"29273772","id":"PMC_29273772","title":"Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo.","date":"2017","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29273772","citation_count":207,"is_preprint":false},{"pmid":"16227602","id":"PMC_16227602","title":"Identification and functional outcome of mRNAs associated with RNA-binding protein TIA-1.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16227602","citation_count":204,"is_preprint":false},{"pmid":"22699908","id":"PMC_22699908","title":"Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22699908","citation_count":199,"is_preprint":false},{"pmid":"8576255","id":"PMC_8576255","title":"Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8576255","citation_count":196,"is_preprint":false},{"pmid":"12486009","id":"PMC_12486009","title":"The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5' splice sites.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12486009","citation_count":189,"is_preprint":false},{"pmid":"21979918","id":"PMC_21979918","title":"Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21979918","citation_count":182,"is_preprint":false},{"pmid":"10938105","id":"PMC_10938105","title":"The RNA-binding protein TIA-1 is a novel mammalian splicing regulator acting through intron sequences adjacent to a 5' splice site.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10938105","citation_count":178,"is_preprint":false},{"pmid":"1326761","id":"PMC_1326761","title":"Identification and functional characterization of a TIA-1-related nucleolysin.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1326761","citation_count":173,"is_preprint":false},{"pmid":"12885872","id":"PMC_12885872","title":"Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12885872","citation_count":170,"is_preprint":false},{"pmid":"16581801","id":"PMC_16581801","title":"Translational control of cytochrome c by RNA-binding proteins TIA-1 and HuR.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16581801","citation_count":167,"is_preprint":false},{"pmid":"14769925","id":"PMC_14769925","title":"Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14769925","citation_count":166,"is_preprint":false},{"pmid":"12414941","id":"PMC_12414941","title":"Cell proteins TIA-1 and TIAR interact with the 3' stem-loop of the West Nile virus complementary minus-strand RNA and facilitate virus replication.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12414941","citation_count":156,"is_preprint":false},{"pmid":"28257633","id":"PMC_28257633","title":"miR-19a promotes colorectal cancer proliferation and migration by targeting TIA1.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28257633","citation_count":154,"is_preprint":false},{"pmid":"7544399","id":"PMC_7544399","title":"Fas-activated serine/threonine kinase (FAST) phosphorylates TIA-1 during Fas-mediated apoptosis.","date":"1995","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7544399","citation_count":153,"is_preprint":false},{"pmid":"18775331","id":"PMC_18775331","title":"Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18775331","citation_count":131,"is_preprint":false},{"pmid":"26738979","id":"PMC_26738979","title":"TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress-induced apoptosis.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26738979","citation_count":125,"is_preprint":false},{"pmid":"23401021","id":"PMC_23401021","title":"Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1.","date":"2013","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23401021","citation_count":124,"is_preprint":false},{"pmid":"12855701","id":"PMC_12855701","title":"The proximal region of the 3'-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12855701","citation_count":123,"is_preprint":false},{"pmid":"33619090","id":"PMC_33619090","title":"TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33619090","citation_count":122,"is_preprint":false},{"pmid":"9176382","id":"PMC_9176382","title":"TIA-1 expression in lymphoid neoplasms. Identification of subsets with cytotoxic T lymphocyte or natural killer cell differentiation.","date":"1997","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9176382","citation_count":117,"is_preprint":false},{"pmid":"11514562","id":"PMC_11514562","title":"TIA-1 and TIAR activate splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on their own pre-mRNAs.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11514562","citation_count":115,"is_preprint":false},{"pmid":"11756181","id":"PMC_11756181","title":"Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11756181","citation_count":101,"is_preprint":false},{"pmid":"29429924","id":"PMC_29429924","title":"The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29429924","citation_count":96,"is_preprint":false},{"pmid":"23348830","id":"PMC_23348830","title":"Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing.","date":"2013","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/23348830","citation_count":95,"is_preprint":false},{"pmid":"7512092","id":"PMC_7512092","title":"Expression of perforin, granzyme A and TIA-1 by human uterine CD56+ NK cells implies they are activated and capable of effector functions.","date":"1993","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7512092","citation_count":95,"is_preprint":false},{"pmid":"30465259","id":"PMC_30465259","title":"TIA1 regulates the generation and response to toxic tau oligomers.","date":"2018","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/30465259","citation_count":90,"is_preprint":false},{"pmid":"18456862","id":"PMC_18456862","title":"A systematic analysis of intronic sequences downstream of 5' splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation.","date":"2008","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/18456862","citation_count":87,"is_preprint":false},{"pmid":"8871565","id":"PMC_8871565","title":"Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8871565","citation_count":86,"is_preprint":false},{"pmid":"29298433","id":"PMC_29298433","title":"TIA-1 Self-Multimerization, Phase Separation, and Recruitment into Stress Granules Are Dynamically Regulated by Zn2.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29298433","citation_count":85,"is_preprint":false},{"pmid":"29457785","id":"PMC_29457785","title":"TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29457785","citation_count":83,"is_preprint":false},{"pmid":"9166283","id":"PMC_9166283","title":"Cytotoxicity and apoptosis in human renal allografts: identification, distribution, and quantitation of cells with a cytotoxic granule protein GMP-17 (TIA-1) and cells with fragmented nuclear DNA.","date":"1997","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9166283","citation_count":78,"is_preprint":false},{"pmid":"24682828","id":"PMC_24682828","title":"Structure, dynamics and RNA binding of the multi-domain splicing factor TIA-1.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24682828","citation_count":75,"is_preprint":false},{"pmid":"17135269","id":"PMC_17135269","title":"Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17135269","citation_count":72,"is_preprint":false},{"pmid":"8506945","id":"PMC_8506945","title":"Cytotoxic effector cell granules recognized by the monoclonal antibody TIA-1 are present in CD8+ lymphocytes in lymph nodes of human immunodeficiency virus-1-infected patients.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8506945","citation_count":72,"is_preprint":false},{"pmid":"21189287","id":"PMC_21189287","title":"TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21189287","citation_count":71,"is_preprint":false},{"pmid":"16278295","id":"PMC_16278295","title":"Identification of the sequence determinants mediating the nucleo-cytoplasmic shuttling of TIAR and TIA-1 RNA-binding proteins.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16278295","citation_count":71,"is_preprint":false},{"pmid":"15280467","id":"PMC_15280467","title":"Herpes simplex virus 1 induces cytoplasmic accumulation of TIA-1/TIAR and both synthesis and cytoplasmic accumulation of tristetraprolin, two cellular proteins that bind and destabilize AU-rich RNAs.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15280467","citation_count":71,"is_preprint":false},{"pmid":"25224594","id":"PMC_25224594","title":"Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance.","date":"2014","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25224594","citation_count":70,"is_preprint":false},{"pmid":"24981173","id":"PMC_24981173","title":"Functional role of Tia1/Pub1 and Sup35 prion domains: directing protein synthesis machinery to the tubulin cytoskeleton.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24981173","citation_count":67,"is_preprint":false},{"pmid":"24696465","id":"PMC_24696465","title":"The stress granule component TIA-1 binds tick-borne encephalitis virus RNA and is recruited to perinuclear sites of viral replication to inhibit viral translation.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24696465","citation_count":64,"is_preprint":false},{"pmid":"10029454","id":"PMC_10029454","title":"The expression of TIA-1+ cytolytic-type granules and other cytolytic lymphocyte-associated markers in CD30+ anaplastic large cell lymphomas (ALCL): correlation with morphology, immunophenotype, ultrastructure, and clinical features.","date":"1999","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10029454","citation_count":63,"is_preprint":false},{"pmid":"21957303","id":"PMC_21957303","title":"Poliovirus unlinks TIA1 aggregation and mRNA stress granule formation.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21957303","citation_count":62,"is_preprint":false},{"pmid":"17711853","id":"PMC_17711853","title":"T-cell intracellular antigen-1 (TIA-1)-induced translational silencing promotes the decay of selected mRNAs.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17711853","citation_count":61,"is_preprint":false},{"pmid":"17488725","id":"PMC_17488725","title":"Two isoforms of the T-cell intracellular antigen 1 (TIA-1) splicing factor display distinct splicing regulation activities. Control of TIA-1 isoform ratio by TIA-1-related protein.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17488725","citation_count":61,"is_preprint":false},{"pmid":"19805546","id":"PMC_19805546","title":"Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19805546","citation_count":58,"is_preprint":false},{"pmid":"28904350","id":"PMC_28904350","title":"Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28904350","citation_count":57,"is_preprint":false},{"pmid":"17456059","id":"PMC_17456059","title":"The number of tumour-infiltrating TIA-1+ cytotoxic T cells but not FOXP3+ regulatory T cells predicts outcome in diffuse large B-cell lymphoma.","date":"2007","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/17456059","citation_count":57,"is_preprint":false},{"pmid":"8823683","id":"PMC_8823683","title":"Mechanisms of lysis by activated cytotoxic cells expressing perforin and granzyme-B genes and the protein TIA-1 in muscle biopsies of myositis.","date":"1996","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8823683","citation_count":54,"is_preprint":false},{"pmid":"29340095","id":"PMC_29340095","title":"Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29340095","citation_count":48,"is_preprint":false},{"pmid":"18768985","id":"PMC_18768985","title":"Mutation of mapped TIA-1/TIAR binding sites in the 3' terminal stem-loop of West Nile virus minus-strand RNA in an infectious clone negatively affects genomic RNA amplification.","date":"2008","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/18768985","citation_count":45,"is_preprint":false},{"pmid":"29216908","id":"PMC_29216908","title":"Clinical and neuropathological features of ALS/FTD with TIA1 mutations.","date":"2017","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/29216908","citation_count":43,"is_preprint":false},{"pmid":"25519906","id":"PMC_25519906","title":"Post-transcriptional regulation of programmed cell death 4 (PDCD4) mRNA by the RNA-binding proteins human antigen R (HuR) and T-cell intracellular antigen 1 (TIA1).","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25519906","citation_count":42,"is_preprint":false},{"pmid":"24659297","id":"PMC_24659297","title":"Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue.","date":"2014","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24659297","citation_count":41,"is_preprint":false},{"pmid":"20980400","id":"PMC_20980400","title":"TIAR and TIA-1 mRNA-binding proteins co-aggregate under conditions of rapid oxygen decline and extreme hypoxia and suppress the HIF-1α pathway.","date":"2010","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20980400","citation_count":40,"is_preprint":false},{"pmid":"36112647","id":"PMC_36112647","title":"ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36112647","citation_count":37,"is_preprint":false},{"pmid":"17580305","id":"PMC_17580305","title":"Nuclear protein TIA-1 regulates COL2A1 alternative splicing and interacts with precursor mRNA and genomic DNA.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17580305","citation_count":37,"is_preprint":false},{"pmid":"28003185","id":"PMC_28003185","title":"TIA-1 Is a Functional Prion-Like Protein.","date":"2017","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/28003185","citation_count":36,"is_preprint":false},{"pmid":"8176212","id":"PMC_8176212","title":"Intron-exon organization and chromosomal localization of the human TIA-1 gene.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8176212","citation_count":35,"is_preprint":false},{"pmid":"22154808","id":"PMC_22154808","title":"Three RNA recognition motifs participate in RNA recognition and structural organization by the pro-apoptotic factor TIA-1.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22154808","citation_count":34,"is_preprint":false},{"pmid":"32327969","id":"PMC_32327969","title":"Reduction of the RNA Binding Protein TIA1 Exacerbates Neuroinflammation in Tauopathy.","date":"2020","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32327969","citation_count":32,"is_preprint":false},{"pmid":"29599744","id":"PMC_29599744","title":"Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features.","date":"2018","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29599744","citation_count":31,"is_preprint":false},{"pmid":"12533540","id":"PMC_12533540","title":"TIA-1 or TIAR is required for DT40 cell viability.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12533540","citation_count":31,"is_preprint":false},{"pmid":"24566137","id":"PMC_24566137","title":"HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24566137","citation_count":31,"is_preprint":false},{"pmid":"33621982","id":"PMC_33621982","title":"Tandem RNA binding sites induce self-association of the stress granule marker protein TIA-1.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33621982","citation_count":31,"is_preprint":false},{"pmid":"10208460","id":"PMC_10208460","title":"Assessment and diagnostic utility of the cytotoxic T-lymphocyte phenotype using the specific markers granzyme-B and TIA-1 in esophageal mucosal biopsies.","date":"1999","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10208460","citation_count":31,"is_preprint":false},{"pmid":"11385223","id":"PMC_11385223","title":"Identification of TIA-1+ and granzyme B+ cytotoxic T cells in lichen sclerosus et atrophicus.","date":"2001","source":"Dermatology (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/11385223","citation_count":30,"is_preprint":false},{"pmid":"28775379","id":"PMC_28775379","title":"TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28775379","citation_count":27,"is_preprint":false},{"pmid":"16890199","id":"PMC_16890199","title":"Control of the ATP synthase beta subunit expression by RNA-binding proteins TIA-1, TIAR, and HuR.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16890199","citation_count":27,"is_preprint":false},{"pmid":"8396236","id":"PMC_8396236","title":"The developmentally-regulated Drosophila gene rox8 encodes an RRM-type RNA binding protein structurally related to human TIA-1-type nucleolysins.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8396236","citation_count":27,"is_preprint":false},{"pmid":"29496454","id":"PMC_29496454","title":"Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29496454","citation_count":25,"is_preprint":false},{"pmid":"10658910","id":"PMC_10658910","title":"TIA-1 positive tumor-infiltrating lymphocytes in nevi and melanomas.","date":"2000","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/10658910","citation_count":25,"is_preprint":false},{"pmid":"19615357","id":"PMC_19615357","title":"Sam68 relocalization into stress granules in response to oxidative stress through complexing with TIA-1.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19615357","citation_count":25,"is_preprint":false},{"pmid":"25461769","id":"PMC_25461769","title":"TIA1 interacts with annexin A7 in regulating vascular endothelial cell autophagy.","date":"2014","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25461769","citation_count":24,"is_preprint":false},{"pmid":"35799293","id":"PMC_35799293","title":"Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.","date":"2022","source":"Military Medical Research","url":"https://pubmed.ncbi.nlm.nih.gov/35799293","citation_count":24,"is_preprint":false},{"pmid":"30144499","id":"PMC_30144499","title":"miR-487a promotes progression of gastric cancer by targeting TIA1.","date":"2018","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/30144499","citation_count":24,"is_preprint":false},{"pmid":"29555582","id":"PMC_29555582","title":"Suberanilohydroxamic acid prevents TGF-β1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation.","date":"2018","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/29555582","citation_count":24,"is_preprint":false},{"pmid":"34750982","id":"PMC_34750982","title":"Amyotrophic lateral sclerosis (ALS) linked mutation in Ubiquilin 2 affects stress granule assembly via TIA-1.","date":"2021","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34750982","citation_count":22,"is_preprint":false},{"pmid":"28193846","id":"PMC_28193846","title":"Protein 4.1R Exon 16 3' Splice Site Activation Requires Coordination among TIA1, Pcbp1, and RBM39 during Terminal Erythropoiesis.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28193846","citation_count":22,"is_preprint":false},{"pmid":"24824036","id":"PMC_24824036","title":"The binding of TIA-1 to RNA C-rich sequences is driven by its C-terminal RRM domain.","date":"2014","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/24824036","citation_count":22,"is_preprint":false},{"pmid":"34310938","id":"PMC_34310938","title":"Disease-associated mutations affect TIA1 phase separation and aggregation in a proline-dependent manner.","date":"2021","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/34310938","citation_count":21,"is_preprint":false},{"pmid":"33025330","id":"PMC_33025330","title":"ALS-Linked Mutant SOD1 Associates with TIA-1 and Alters Stress Granule Dynamics.","date":"2020","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/33025330","citation_count":21,"is_preprint":false},{"pmid":"30865887","id":"PMC_30865887","title":"Genetic Perturbation of TIA1 Reveals a Physiological Role in Fear Memory.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30865887","citation_count":21,"is_preprint":false},{"pmid":"11762949","id":"PMC_11762949","title":"TIA-1 regulates the production of tumor necrosis factor alpha in macrophages, but not in lymphocytes.","date":"2001","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/11762949","citation_count":21,"is_preprint":false},{"pmid":"28184449","id":"PMC_28184449","title":"TIA-1 RRM23 binding and recognition of target oligonucleotides.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28184449","citation_count":20,"is_preprint":false},{"pmid":"36638831","id":"PMC_36638831","title":"Liquid Droplet Aging and Seeded Fibril Formation of the Cytotoxic Granule Associated RNA Binding Protein TIA1 Low Complexity Domain.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/36638831","citation_count":20,"is_preprint":false},{"pmid":"34082786","id":"PMC_34082786","title":"Dynamics of alternative splicing during somatic cell reprogramming reveals functions for RNA-binding proteins CPSF3, hnRNP UL1, and TIA1.","date":"2021","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/34082786","citation_count":20,"is_preprint":false},{"pmid":"8655683","id":"PMC_8655683","title":"Expression of TIA-1 and TIA-2 in T cell malignancies and T cell lymphocytosis.","date":"1996","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8655683","citation_count":20,"is_preprint":false},{"pmid":"29370934","id":"PMC_29370934","title":"Mutation analysis of the TIA1 gene in Chinese patients with amyotrophic lateral sclerosis and frontotemporal dementia.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/29370934","citation_count":19,"is_preprint":false},{"pmid":"11176318","id":"PMC_11176318","title":"TIA1 and mast cell tryptase in food allergy of children: increase of intraepithelial lymphocytes expressing TIA1 associates with allergy.","date":"2001","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/11176318","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51893,"output_tokens":10049,"usd":0.153207,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20533,"output_tokens":6274,"usd":0.129757,"stage2_stop_reason":"end_turn"},"total_usd":0.282964,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TIA-1 acts downstream of eIF-2alpha phosphorylation to promote assembly of stress granules (SGs). A phosphomimetic eIF-2alpha mutant (S51D) induces SG assembly, a non-phosphorylatable mutant (S51A) prevents it, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation, placing TIA-1 downstream of eIF-2alpha in the pathway.\",\n      \"method\": \"Phosphomimetic/non-phosphorylatable eIF-2alpha mutant transfection, dominant-negative TIA-1 truncation mutant, fluorescence microscopy of SG assembly\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (phosphomimetic, non-phosphorylatable, dominant-negative), replicated in multiple labs\",\n      \"pmids\": [\"10613902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Stress granule assembly is mediated by prion-like aggregation of TIA-1's glutamine-rich prion-related domain (PRD). The PRD is required for SG recruitment and exhibits concentration-dependent aggregation inhibited by HSP70; substitution of the PRD with the yeast prion domain SUP35-NM reconstitutes SG assembly. MEFs lacking TIA-1 show impaired SG formation with normal eIF2alpha phosphorylation, confirming TIA-1 acts downstream of eIF2alpha.\",\n      \"method\": \"Truncation/deletion mutants, PRD domain swap with yeast SUP35-NM, TIA-1 knockout MEFs, protease resistance assay, HSP70 co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution with heterologous prion domain, multiple orthogonal methods, KO MEF validation\",\n      \"pmids\": [\"15371533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 and PABP-I dynamically and continuously shuttle in and out of stress granules, as demonstrated by FRAP of GFP-tagged proteins in live cells. Drugs that stabilize polysomes (emetine) dissolve preformed SGs, while drugs that destabilize polysomes (puromycin) promote SG assembly, indicating SGs and polysomes exist in equilibrium.\",\n      \"method\": \"GFP-tagged TIA-1 live-cell imaging, FRAP, pharmacological manipulation (emetine, puromycin)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct FRAP quantification in live cells, multiple pharmacological controls, replicated concept across labs\",\n      \"pmids\": [\"11121440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 functions as a translational silencer of TNF-alpha. In TIA-1 knockout macrophages, TNF-alpha protein production is significantly increased without change in transcript levels or half-life, but with increased polysome association of TNF-alpha mRNA, indicating TIA-1 inhibits translation rather than mRNA stability.\",\n      \"method\": \"Homologous recombination knockout mice, polysome fractionation, LPS stimulation of macrophages, intracellular flow cytometry, ELISA\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with polysome fractionation and multiple readouts; independently confirmed in subsequent studies\",\n      \"pmids\": [\"10921895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 regulates alternative pre-mRNA splicing by binding U-rich sequences downstream of 5' splice sites and facilitating U1 snRNP recruitment, demonstrated for Drosophila msl-2 and human Fas pre-mRNAs.\",\n      \"method\": \"In vitro splicing assays, UV cross-linking, immunoprecipitation, overexpression in cultured cells, U1 snRNP recruitment assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro splicing reconstitution plus in vivo overexpression, replicated by multiple independent labs\",\n      \"pmids\": [\"11106748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RNA binding specificity of TIA-1 is mediated primarily by RRM2, which selectively binds uridylate-rich sequences; replacing uridylates with cytidines abolishes binding. RRM3 can bind a broad population of cellular RNAs, while RRM1 does not bind RNA due to negatively charged residues in the RNP1 octamer.\",\n      \"method\": \"In vitro SELEX (selection/amplification from random RNA pools), filter binding assays, mutational analysis of individual RRM domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro SELEX and mutagenesis with quantitative binding constants, single lab but rigorous biochemical dissection\",\n      \"pmids\": [\"8576255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIA-1 interacts directly with the U1 snRNP protein U1-C via its Q-rich domain (enhanced by RRM1), and RRM2+3 are required for pre-mRNA binding. This direct TIA-1/U1-C interaction facilitates recruitment of U1 snRNP to weak 5' splice sites.\",\n      \"method\": \"Co-precipitation assays with recombinant proteins, domain deletion analysis, in vitro U1 snRNP recruitment assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct protein-protein interaction mapped by co-precipitation with deletion mutants and functional validation in splicing assays\",\n      \"pmids\": [\"12486009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 promotes Fas exon 6 inclusion by enhancing U1 snRNP binding to the 5' splice site of intron 6, which in turn facilitates U2AF binding to the 3' splice site of intron 5 (exon definition). This opposes PTB-mediated exon skipping via an exonic splicing silencer.\",\n      \"method\": \"In vitro splicing assays, U1 snRNP and U2AF binding assays, PTB competition experiments, reporter minigene transfection\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of spliceosome assembly steps, multiple orthogonal approaches, independently validated\",\n      \"pmids\": [\"16109372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fas-activated serine/threonine kinase (FAST) is activated during Fas-mediated apoptosis and directly phosphorylates TIA-1. FAST dephosphorylation and concomitant activation precedes TIA-1 phosphorylation and DNA fragmentation, placing FAST upstream of TIA-1 in Fas apoptotic signaling.\",\n      \"method\": \"Kinase activation assays, phosphorylation of TIA-1 by immunoprecipitated FAST kinase in vitro, temporal analysis relative to DNA fragmentation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay demonstrating direct phosphorylation, temporal epistasis established\",\n      \"pmids\": [\"7544399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIA-1 binds the AU-rich element in the COX-2 mRNA 3'UTR and functions as a translational silencer of COX-2. TIA-1 null fibroblasts produce significantly more COX-2 protein without changes in transcription or mRNA turnover; colon cancer cells with COX-2 overexpression show defective TIA-1 binding.\",\n      \"method\": \"RNA binding studies, TIA-1 null fibroblasts (KO mice), COX-2 transcript stability assays, polysome analysis, in vitro RNA pulldown\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts confirming translational (not stability) regulation\",\n      \"pmids\": [\"12885872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 associates with a broad set of target mRNAs containing a U-rich bipartite motif (30-37 nt) predominantly in the 3'UTR, and represses their translation. The motif was identified by immunoprecipitation of TIA-1-RNA complexes followed by microarray analysis; RNAi knockdown of TIA-1 de-represses target mRNA translation.\",\n      \"method\": \"Immunoprecipitation of TIA-1-RNA complexes, microarray analysis, RT-PCR validation, biotinylated RNA pulldown/Western blot, RNAi knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation + microarray + RNAi with translational readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16227602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TIA-1 functions as a translational repressor of cytochrome c mRNA by binding its 3'UTR (proximal region), opposing the translational activator HuR. TIA-1 silencing dramatically increases cytochrome c translation; following ER stress, cytochrome c mRNA exits polysomes and translation declines.\",\n      \"method\": \"RNA-binding protein immunoprecipitation, siRNA knockdown, polysome fractionation, metabolic labeling of nascent cytochrome c protein\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with polysome fractionation, single lab with multiple readouts\",\n      \"pmids\": [\"16581801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FAST kinase synergizes with TIA-1/TIAR to promote Fas exon 6 inclusion. Depletion of FAST K causes exon 6 skipping; FAST K overexpression effects are suppressed by TIA-1/TIAR depletion. In vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding, suggesting phosphorylation modulates protein-protein interactions at the spliceosome.\",\n      \"method\": \"siRNA depletion of FAST K, Fas minigene reporter assays, in vitro phosphorylation of TIA-1 by FAST K, U1 snRNP recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with functional splicing consequence, epistasis via knockdown, single lab\",\n      \"pmids\": [\"17135269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIA-1-induced translational silencing promotes mRNA decay via both the 5'-3' (DCP2-dependent) and 3'-5' (exosome Rrp46-dependent) decay pathways. TIA-1-mediated decay requires polysome disassembly (inhibited by cycloheximide/emetine but not puromycin); tethering TIA-1 to a reporter mRNA promotes its decay.\",\n      \"method\": \"siRNA knockdown of decay pathway components (DCP2, Rrp46), reporter mRNA tethering assay, polysome-stabilizing/destabilizing drugs, gene array analysis in TIA-1 KO macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tethering assay plus siRNA epistasis of decay pathway components, single lab\",\n      \"pmids\": [\"17711853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RSK2 directly interacts with the prion-related domain (PRD) of TIA-1 via its N-terminal kinase domain and co-localizes in stress granules in a codependent manner. Silencing RSK2 decreases cell survival under stress. Mitogen releases RSK2 from SGs for nuclear import, and nuclear accumulation of RSK2 depends on TIA-1.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, domain mapping with RSK2 N-terminal kinase domain, siRNA knockdown of RSK2, live-cell imaging of SG colocalization, nuclear fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, siRNA knockdown with survival phenotype, single lab\",\n      \"pmids\": [\"18775331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIA-1 and TIAR bind the 5' end of 5'TOP mRNAs upon amino acid starvation (requiring GCN2 activation and mTOR inactivation) and arrest translation at the initiation step, causing 5'TOP mRNA polysome release and accumulation in stress granules.\",\n      \"method\": \"RNA immunoprecipitation, polysome fractionation, siRNA knockdown of TIA-1/TIAR, GCN2 inhibition, mTOR inhibition/activation, stress granule microscopy\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, polysome fractionation, pathway epistasis (GCN2/mTOR), multiple orthogonal methods in one study\",\n      \"pmids\": [\"21979918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIA-1 (and TIAR) bind specifically to the 3' terminal stem-loop of West Nile virus minus-strand RNA via RRM2. WNV growth is less efficient in TIAR knockout cells but not in cells lacking other RNA virus susceptibility factors; reconstitution of TIAR restored WNV growth, suggesting TIA-1/TIAR facilitate flavivirus genome RNA replication.\",\n      \"method\": \"RNA affinity column purification, UV cross-linking/immunoprecipitation, recombinant protein competition gel-shift assays, TIAR KO cell lines, reconstitution experiments, virus growth assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding mapped to RRM2 with Kd values, KO and reconstitution with functional viral replication assay\",\n      \"pmids\": [\"12414941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA-1 binds tick-borne encephalitis virus (TBEV) RNA in infected cells and is recruited to perinuclear sites of viral replication, depleting SGs. TIA-1 inhibits TBEV at the level of first-round viral translation, as TIA-1 KO fibroblasts show increased luciferase activity from a TBEV replicon at early time points.\",\n      \"method\": \"RNA immunoprecipitation in TBEV-infected cells, siRNA knockdown, TIA-1 KO MEFs, TBEV-luciferase replicon assay, immunofluorescence microscopy\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells, replicon functional assay, RIP, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"24696465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA-1 NMR solution structure (RRM2-RRM3) reveals RRM2 adopts a canonical RRM fold while RRM3 is preceded by a non-canonical helix α0. All three RRMs are largely independent in the absence of RNA but adopt a compact arrangement upon RNA binding. RRM2,3 binds pyrimidine-rich RNA with nanomolar affinity; RRM1 has little intrinsic RNA binding affinity.\",\n      \"method\": \"NMR spectroscopy (solution structure of RRM2-RRM3), SAXS, isothermal titration calorimetry (ITC), RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination with SAXS and ITC functional validation, single lab but multiple orthogonal biophysical methods\",\n      \"pmids\": [\"24682828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIA-1 oxidation by reactive oxygen species (H2O2) inhibits stress granule assembly. When cells face concurrent ER stress and oxidative stress, ROS-oxidized TIA1 cannot form SGs, leading to enhanced apoptosis. This demonstrates that TIA1's SG-nucleating activity is redox-regulated.\",\n      \"method\": \"H2O2 treatment combined with ER stress (tunicamycin), SG formation assays by immunofluorescence, TIA1 oxidation biochemical analysis, cell viability/apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct oxidative modification of TIA1 with functional SG assembly and apoptosis readouts, single lab\",\n      \"pmids\": [\"26738979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tau interacts with TIA1 in brain tissue, and tau regulates the distribution of TIA1 and accelerates stress granule formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while TIA1 overexpression induces tau misfolding and neurodegeneration.\",\n      \"method\": \"Co-immunoprecipitation from brain tissue, TIA1 interactome analysis (MS), TIA1 KO/KD in hippocampal neurons, tau misfolding assays, pharmacological SG inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from brain tissue, KO/KD with cellular toxicity phenotype, single lab with multiple methods\",\n      \"pmids\": [\"27160897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALS/FTD-associated mutations in the TIA1 low-complexity domain (LCD), including P362L, increase TIA1's propensity to undergo phase transition, delay SG disassembly, promote accumulation of non-dynamic SGs harboring TDP-43, and render TDP-43 less mobile and insoluble.\",\n      \"method\": \"Patient-derived genetic analysis, phase separation assays in vitro, live-cell SG dynamics (FRAP), TDP-43 mobility and solubility assays, postmortem neuropathology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro phase separation, FRAP in live cells, multiple patient mutations, neuropathology correlation; replicated by subsequent structural studies\",\n      \"pmids\": [\"28817800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Recombinant TIA-1 undergoes rapid multimerization and phase separation in the presence of divalent zinc (Zn2+), reversible by the zinc chelator TPEN. In arsenite-stressed cells, Zn2+ is released before SG formation, and TPEN inhibits formation and maintenance of TIA-1-positive SGs, identifying Zn2+ as a physiological second messenger for TIA-1 multimerization.\",\n      \"method\": \"Recombinant TIA-1 phase separation assay with ZnCl2, TPEN chelation rescue, Zn2+ release measurement in arsenite-treated cells, immunofluorescence SG assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with recombinant protein and functional in-cell validation, single lab\",\n      \"pmids\": [\"29298433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Double knockout of TIA1 and TIAL1 increases target mRNA abundance proportional to binding site number and causes accumulation of aberrantly spliced mRNAs subject to NMD. Loss of PRKRA by mis-splicing activates PKR (EIF2AK2) and triggers spontaneous SG formation; ectopic PRKRA cDNA or EIF2AK2 knockout in DKO cells rescues this phenotype.\",\n      \"method\": \"CRISPR double KO of TIA1/TIAL1, PAR-CLIP for target site mapping, RNA-seq for splicing/abundance, ectopic PRKRA cDNA rescue, EIF2AK2 KO epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — double KO with PAR-CLIP target mapping, epistasis rescue with cDNA and second KO, multiple orthogonal methods\",\n      \"pmids\": [\"29429924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 and TIAR continuously shuttle between nucleus and cytoplasm in a transcription-dependent manner. RRM2 and the first half of the auxiliary region mediate nuclear accumulation; RRM3 mediates nuclear export. Both RRMs contribute to localization through their RNA-binding capacity. Nuclear export is Ran-GTP-independent and CRM1-independent.\",\n      \"method\": \"Domain truncation/mutation analysis, leptomycin B (CRM1 inhibitor) treatment, Ran-GTP depletion, transcription inhibitors, fluorescence microscopy of GFP-tagged constructs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutants with functional localization readouts and pathway inhibitors, single lab\",\n      \"pmids\": [\"16278295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIA-1 binds to AU-rich sequences in COL2A1 intron 2, modulates alternative splicing of COL2A1 exon 2, and also interacts with the equivalent single-stranded DNA sequence in vivo (confirmed by chromatin immunoprecipitation), suggesting a dual role at both transcription and pre-mRNA splicing levels.\",\n      \"method\": \"Minigene splicing assays, RNP immunoprecipitation for pre-mRNA binding, chromatin immunoprecipitation (ChIP) with RNase step, competition assays for DNA vs RNA binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNP-IP and ChIP with functional splicing readout, single lab with multiple approaches\",\n      \"pmids\": [\"17580305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TIA-1 and TIAR binding sites in the West Nile virus 3' minus-strand stem-loop RNA were mapped to short AU sequences (UAAUU) in internal loops. Infectious clone RNAs with deleted/substituted binding sites showed decreased TIAR/TIA-1 binding efficiency correlated with decreased intracellular genomic RNA levels and virus production, implicating TIA-1/TIAR binding in asymmetric amplification of genomic RNA from the minus-strand template.\",\n      \"method\": \"Infectious clone RNA mutagenesis, in vitro protein binding assays, plaque assays, intracellular RNA quantification by qRT-PCR\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis of viral RNA binding sites with functional viral replication readout, single lab\",\n      \"pmids\": [\"18768985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 is recruited to stress granules under oxidative stress through direct complex formation with TIA-1. Domains aa269-321 and the KH domain of Sam68 are essential for SG recruitment, but Sam68 knockdown does not impair SG assembly.\",\n      \"method\": \"Co-immunoprecipitation of Sam68 and TIA-1, domain deletion mapping, siRNA knockdown of Sam68, immunofluorescence of SG markers under oxidative stress\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with domain mapping, single lab, no reciprocal IP with TIA-1\",\n      \"pmids\": [\"19615357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TIA1 prevents skipping of SMN2 exon 7 in a novel context where intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. Any single RRM combined with the Q domain is sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. TIA1 counteracts the inhibitory effect of PTB on SMN exon 7 splicing.\",\n      \"method\": \"In vivo splicing assays with TIA1/TIAR expression, domain deletion/chimeric protein analysis, co-expression with PTB, RT-PCR of endogenous SMN2 exon 7 splicing\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo splicing assays with systematic domain dissection and epistasis with PTB, single lab\",\n      \"pmids\": [\"21189287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TDP-43 differentially regulates key SG components: controlled aggregation of TIA-1 is disrupted in the absence of TDP-43, resulting in slowed SG formation. TDP-43 also regulates G3BP mRNA levels. The disease mutation TDP-43(R361S) is a loss-of-function mutation for SG formation and alters TIA-1 and G3BP levels.\",\n      \"method\": \"TDP-43 siRNA knockdown, oxidative stress/heat shock/thapsigargin-induced SG assays, immunofluorescence, Western blot for TIA-1 and G3BP, TDP-43 mutant expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with functional SG readout and mutation analysis, single lab\",\n      \"pmids\": [\"21257637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Welander distal myopathy (WDM) is caused by the E384K mutation in TIA1's Q-rich domain. Mutant TIA1 causes increased SG abundance and slower FRAP kinetics in HeLa cells, consistent with altered SG dynamics. The E384K mutation is in the domain that interacts with U1-C splicing factor, and WDM patients have increased SMN2 exon 7 skipping.\",\n      \"method\": \"Genetic sequencing/linkage analysis, Western blot and immunofluorescence of WDM muscle biopsies, high-content SG quantification in HeLa cells, FRAP, RT-PCR of SMN2 splicing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and SG quantification with identified mutation, multiple methods but single patient cohort study\",\n      \"pmids\": [\"23401021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In yeast, Tia1/Pub1 forms a prion and cooperates with Sup35/eRF3 to establish a two-protein self-propagating state along tubulin cytoskeleton. A tubulin-associated complex containing Pub1 and Sup35 oligomers (plus TUB1 mRNA and translation machinery) depends on prion domains; PUB1 disruption leads to cytoskeletal defects.\",\n      \"method\": \"Yeast prion assays, fluorescence microscopy of line structures along tubulin, genetic disruption of PUB1, co-purification of Pub1/Sup35/TUB1 mRNA complex\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast prion assay with genetic and biochemical validation; ortholog study in S. cerevisiae consistent with mammalian TIA1 prion function\",\n      \"pmids\": [\"24981173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA-1 RRM3 binds both C-rich and U-rich sequences with micromolar affinity, and in the context of full-length TIA-1, RRM3 significantly enhances binding to C-rich RNA (including 5'TOP sequences), as demonstrated by STD-NMR and biotinylated RNA pulldown.\",\n      \"method\": \"STD-NMR, surface plasmon resonance (SPR), biotinylated RNA pulldown/Western blot with full-length TIA-1 and isolated domains\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR and SPR biophysical characterization of RNA binding, single lab with multiple methods\",\n      \"pmids\": [\"24824036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of TIA-1 RRM2 in complex with DNA at 2.3 Å resolution provides the first atomic-resolution structure of any TIA protein RRM with oligonucleotide. SAXS shows TIA-1 RRM23 adopts a compact structure upon complex formation with target RNA or DNA; both RRMs engage the 10-nt target sequence.\",\n      \"method\": \"X-ray crystallography (2.3 Å), SAXS, in vitro binding assays, site-directed mutagenesis (Lys274)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination with SAXS and functional binding validation, single lab but high-resolution structural evidence\",\n      \"pmids\": [\"28184449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIA1 interaction with RNA and the presence of TIA1 protein together are sufficient to drive phase separation of tau at physiological concentrations without crowding agents. Phase separation of tau with TIA1 generates abundant tau oligomers that are significantly more toxic than tau aggregates formed with RNA alone, identifying a mechanism for generating toxic tau species.\",\n      \"method\": \"In vitro phase separation assay with recombinant proteins and RNA, tau oligomer toxicity assays, comparison with other RBPs (G3BP1) and crowding agents (PEG)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical reconstitution in vitro with multiple conditions, toxicity readout, single lab\",\n      \"pmids\": [\"33619090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tandem RNA binding sites (not single sites) are required to enhance TIA-1 phase separation. Single-stranded RNA and DNA with tandem binding sites efficiently promote both liquid-liquid phase separation and amyloid-like fibril formation of full-length TIA-1 in vitro; this is finely tuned by protein:binding site stoichiometry.\",\n      \"method\": \"In vitro phase separation assays with designed and native RNA/DNA sequences, fibril formation assays, SAXS for conformational analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic variation of binding site number/stoichiometry, single lab\",\n      \"pmids\": [\"33621982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NMR analysis and molecular dynamics simulations reveal that TIA1 PLD dynamic structure is determined by physicochemical properties in 5-residue units. ALS mutations P362L and A381T enhance self-assembly by inducing β-sheet interactions and highly condensed assemblies (promoting irreversible amyloid fibrillization), while WDM mutation E384K attenuates sticky properties.\",\n      \"method\": \"NMR analysis, molecular dynamics simulations, 3D electron crystallography, biochemical aggregation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR + electron crystallography + MD simulations with biochemical validation, multiple disease mutations characterized\",\n      \"pmids\": [\"36112647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIA1 (Tia1) controls translational silencing of p53 mRNA and its localization to stress granules in activated B lymphocytes. Upon DNA damage, p53 mRNA is released from TIA1-containing stress granules and associates with polyribosomes for CAP-independent translation. Tia1 dissociation from mRNA targets is part of the ATM-dependent DNA damage response.\",\n      \"method\": \"RIP (TIA1), polyribosome fractionation, stress granule isolation, RNA granule localization imaging, knockout/knockdown analysis in primary B cells, global translation profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP with polysome fractionation and granule localization, functional rescue in primary cells, single lab\",\n      \"pmids\": [\"28904350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA1 interacts with annexin A7 (ANXA7), and this interaction regulates TIA1 phosphorylation. Treatment with ABO (ANXA7 inhibitor) promotes TIA1-ANXA7 interaction and inhibits TIA1 phosphorylation in HUVECs, leading to increased expression of ATG13 (pro-autophagy) via FLJ11812 processing.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, ABO treatment, Western blot for phospho-TIA1, autophagy marker quantification\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid and Co-IP with pharmacological intervention, single lab, indirect phosphorylation readout\",\n      \"pmids\": [\"25461769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIA1 N-terminal region coordinates with Pcbp1 and RBM39 to activate 3' splice site of protein 4.1R exon 16. TIA1 and Pcbp1 bind a UUUUCCCCCC motif between branch point and 3' splice site; together with RBM39, they promote U2 snRNP recruitment and spliceosome A complex formation via RBM39-U2AF65-SF3b155 interactions.\",\n      \"method\": \"In vitro splicing assays, RNA binding/UV cross-linking, RNAi knockdown, co-immunoprecipitation of RBM39/TIA1/Pcbp1 complex, U2 snRNP recruitment assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical reconstitution with co-IP of multi-protein complex and functional splicing assays, single lab\",\n      \"pmids\": [\"28193846\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIA-1 is an RNA-binding protein with three RRMs (RRM2 mediates U-rich RNA binding, RRM3 augments binding to C-rich sequences, RRM1 enhances U1-C interaction) and a C-terminal prion-like Q-rich domain that, upon cellular stress, drives liquid-liquid phase separation and aggregation downstream of eIF2alpha phosphorylation to nucleate stress granules where it sequesters and translationally silences target mRNAs; it also promotes inclusion of weak 5' splice sites by directly binding U-rich intronic sequences and recruiting U1 snRNP through a direct RRM1/Q-domain interaction with U1-C; TIA-1 activity is regulated by FAST kinase phosphorylation, Zn2+-induced multimerization, and ROS-mediated oxidation, and disease-associated mutations in its low-complexity domain pathologically enhance phase transition and delay SG disassembly, linking TIA-1 to ALS/FTD and tauopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIA-1 is a multidomain RNA-binding protein that couples mRNA recognition to two cellular functions—translational silencing within stress granules and regulation of alternative pre-mRNA splicing [#0, #4]. RNA recognition is mediated by tandem RRMs: RRM2 selectively binds uridylate-rich sequences while RRM1 lacks intrinsic RNA-binding capacity, and RRM3 augments binding to C-rich and 5'TOP sequences [#5, #32], with crystallographic and NMR/SAXS data showing RRM2-RRM3 collapse into a compact arrangement upon engaging a 10-nucleotide pyrimidine target [#18, #33]. Through these domains TIA-1 binds U-rich bipartite motifs predominantly in 3'UTRs and represses translation of target mRNAs including TNF-alpha, COX-2, cytochrome c, and p53 without altering transcript levels [#3, #9, #10, #11, #37], and this silencing can be coupled to mRNA decay via both 5'-3' and 3'-5' pathways [#13]. Upon eIF2alpha phosphorylation and polysome disassembly, TIA-1 nucleates stress granules through prion-like aggregation of its C-terminal glutamine-rich domain, into and out of which it dynamically shuttles [#0, #1, #2]; this self-assembly is promoted by tandem RNA binding sites and by Zn2+-induced multimerization, and is inhibited by ROS-mediated oxidation [#22, #19, #35]. In the nucleus TIA-1 promotes inclusion of weak 5' splice sites by binding U-rich intronic sequences and recruiting U1 snRNP through a direct interaction between its Q-rich domain and U1-C, facilitating exon definition (e.g. Fas exon 6, SMN2 exon 7) and opposing PTB-mediated skipping [#4, #6, #7, #28]. TIA-1 activity is modulated by FAST kinase phosphorylation, which enhances U1 snRNP recruitment at the spliceosome [#8, #12]. Disease-associated mutations in the low-complexity/Q-rich domain pathologically alter phase behavior: ALS/FTD mutations (P362L, A381T) enhance beta-sheet-driven self-assembly and delay disassembly of TDP-43-containing stress granules, whereas the Welander distal myopathy mutation E384K alters SG dynamics and SMN2 splicing [#21, #36, #30]. TIA-1 also drives toxic tau oligomer formation and accelerates tau misfolding, linking it to tauopathy [#20, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that TIA-1 is a substrate of an apoptotic signaling kinase, providing the first link between TIA-1 and regulated post-transcriptional control during Fas-mediated cell death.\",\n      \"evidence\": \"in vitro phosphorylation of TIA-1 by immunoprecipitated FAST kinase with temporal epistasis to DNA fragmentation\",\n      \"pmids\": [\"7544399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"phosphorylation sites not mapped\", \"functional consequence of phosphorylation not defined at this stage\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved which domains confer RNA specificity, showing RRM2 drives U-rich binding while RRM1 is non-binding—defining the modular logic of TIA-1 recognition.\",\n      \"evidence\": \"in vitro SELEX, filter binding, and per-RRM mutational analysis\",\n      \"pmids\": [\"8576255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of specificity not yet resolved\", \"in vivo target spectrum unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed TIA-1 genetically downstream of eIF2alpha phosphorylation in stress granule assembly, establishing it as an effector of the translational stress response.\",\n      \"evidence\": \"phosphomimetic/non-phosphorylatable eIF2alpha mutants and dominant-negative TIA-1 truncation with SG microscopy\",\n      \"pmids\": [\"10613902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"domain responsible for SG nucleation not identified here\", \"molecular nature of aggregation undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined TIA-1's two parallel functions—translational silencing of specific mRNAs and splice-site selection—answering what TIA-1 actually does to its bound RNAs.\",\n      \"evidence\": \"TIA-1 knockout macrophages with polysome fractionation (TNF-alpha); in vitro splicing and U1 recruitment assays (Fas, msl-2); FRAP of GFP-TIA-1 in live cells\",\n      \"pmids\": [\"10921895\", \"11106748\", \"11121440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how silencing and splicing functions are partitioned between compartments unclear\", \"global target set not yet defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the direct protein-protein contact—Q-domain/U1-C—through which TIA-1 recruits U1 snRNP, providing the mechanism for its splicing-enhancer activity.\",\n      \"evidence\": \"co-precipitation of recombinant proteins with domain deletions and in vitro U1 recruitment\",\n      \"pmids\": [\"12486009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural detail of the interaction absent\", \"regulation of the contact unknown at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended TIA-1 RNA recognition to viral templates, showing RRM2-mediated binding to flavivirus minus-strand RNA promotes genome replication.\",\n      \"evidence\": \"RNA affinity purification, gel-shift, TIAR KO and reconstitution with WNV growth assays\",\n      \"pmids\": [\"12414941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of replication enhancement not resolved\", \"single virus family tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Pinned SG assembly on prion-like aggregation of the Q-rich PRD, explaining how TIA-1 physically nucleates granules.\",\n      \"evidence\": \"PRD deletion, swap with yeast SUP35-NM, protease resistance, HSP70 Co-IP, and TIA-1 KO MEFs\",\n      \"pmids\": [\"15371533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"biophysical nature of aggregation (LLPS vs amyloid) not distinguished\", \"regulation of aggregation undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Generalized TIA-1 translational silencing to additional ARE-containing transcripts and a global target motif, with COX-2 implicating TIA-1 loss in cancer.\",\n      \"evidence\": \"TIA-1 null fibroblasts, RNA pulldown, polysome analysis (COX-2); TIA-1-RNA IP plus microarray and RNAi de-repression (global U-rich motif)\",\n      \"pmids\": [\"12885872\", \"16227602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of translational block not defined at codon/initiation level\", \"how silencing relates to SG sequestration unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected splicing enhancement to exon definition and characterized nucleocytoplasmic shuttling, integrating TIA-1's nuclear and cytoplasmic behaviors.\",\n      \"evidence\": \"in vitro reconstitution of U1/U2AF cross-talk at Fas exon 6; domain-mutant localization with CRM1/Ran-independence\",\n      \"pmids\": [\"16109372\", \"16278295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"export receptor for TIA-1 unidentified\", \"signals coupling localization to function unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed FAST kinase phosphorylation tunes TIA-1 splicing activity at the protein-interaction level rather than RNA binding, linking the 1995 kinase substrate finding to function.\",\n      \"evidence\": \"FAST K siRNA, Fas minigene assays, in vitro phosphorylation with U1 recruitment readout; cytochrome c RIP and polysome work opposing HuR\",\n      \"pmids\": [\"17135269\", \"16581801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"phosphosites still unmapped\", \"mechanism by which phosphorylation enhances U1 recruitment unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed silencing is mechanistically coupled to mRNA decay and that TIA-1 can engage DNA, broadening its regulatory range.\",\n      \"evidence\": \"tethering assays with DCP2/Rrp46 siRNA epistasis (decay); ChIP and RNP-IP at COL2A1 (DNA/RNA dual binding)\",\n      \"pmids\": [\"17711853\", \"17580305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether decay is direct or secondary to polysome disassembly unclear\", \"physiological significance of DNA binding undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified RSK2 as a PRD-interacting kinase partner co-regulated with TIA-1 in stress granules, linking SG dynamics to cell survival signaling.\",\n      \"evidence\": \"reciprocal Co-IP, domain mapping, RSK2 siRNA survival phenotype, nuclear fractionation\",\n      \"pmids\": [\"18775331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether RSK2 phosphorylates TIA-1 not established\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Tied TIA-1 silencing to nutrient sensing, showing it arrests 5'TOP mRNA translation downstream of GCN2/mTOR, and revealed TDP-43 dependence of TIA-1 aggregation.\",\n      \"evidence\": \"RIP, polysome fractionation, GCN2/mTOR perturbation (5'TOP); TDP-43 knockdown with SG dynamics and mutant analysis\",\n      \"pmids\": [\"21979918\", \"21257637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how 5'TOP recognition is achieved structurally unclear\", \"TDP-43/TIA-1 interplay mechanism undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided atomic and biophysical structure of the RNA-engaged RRM module and refined RRM3 specificity, explaining how TIA-1 reads pyrimidine-rich targets.\",\n      \"evidence\": \"NMR solution structure of RRM2-RRM3, SAXS, ITC; STD-NMR/SPR for RRM3 C-rich binding\",\n      \"pmids\": [\"24682828\", \"24824036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RRM1 contribution structurally unresolved\", \"PRD structure not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated conserved prion behavior of the TIA-1 ortholog and added a flavivirus-restriction/replication role, situating phase behavior in deep evolutionary and antiviral contexts.\",\n      \"evidence\": \"yeast Pub1 prion assays with Sup35 cooperation; TBEV replicon and KO MEF assays; WNV binding-site mutagenesis with viral RNA quantitation\",\n      \"pmids\": [\"24981173\", \"24696465\", \"18768985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether viral roles are restriction or pro-replication is context-dependent and unresolved\", \"ortholog prion mechanism not directly demonstrated for human TIA-1\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established redox control of SG nucleation and identified tau as a brain interactor whose toxicity depends on TIA-1, opening the neurodegeneration axis.\",\n      \"evidence\": \"H2O2 oxidation with SG/apoptosis assays; brain Co-IP, TIA-1 KO/KD with tau misfolding readouts\",\n      \"pmids\": [\"26738979\", \"27160897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"oxidized residues not mapped\", \"direct vs indirect tau interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined disease mutation mechanism (LCD mutations enhance phase transition and trap TDP-43) and added p53 silencing plus multi-protein splicing roles, unifying biophysics, splicing, and disease.\",\n      \"evidence\": \"patient mutations with in vitro LLPS, FRAP, TDP-43 solubility and neuropathology (P362L); p53 RIP/polysome in B cells; RBM39/Pcbp1/TIA-1 splicing complex reconstitution\",\n      \"pmids\": [\"28817800\", \"28904350\", \"28193846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"link between altered SG dynamics and neuronal death not fully causal\", \"in vivo consequences of mutations not modeled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Zn2+ as a physiological multimerization trigger and used double knockout to reveal that TIA-1/TIAL1 loss drives mis-splicing-induced PKR activation and spontaneous SGs.\",\n      \"evidence\": \"recombinant LLPS with ZnCl2/TPEN and in-cell Zn2+ release; CRISPR DKO with PAR-CLIP, RNA-seq, PRKRA/EIF2AK2 epistasis rescue\",\n      \"pmids\": [\"29298433\", \"29429924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"zinc-binding site on TIA-1 not localized\", \"physiological relevance of the PKR feedback loop in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed tandem RNA binding sites tune TIA-1 phase separation/fibrillization and that TIA-1 directly drives toxic tau oligomer formation, defining how RNA stoichiometry and tau converge on pathological assemblies.\",\n      \"evidence\": \"in vitro LLPS/fibril assays with designed tandem-site RNA/DNA and SAXS; reconstituted tau-TIA-1 phase separation with oligomer toxicity assays\",\n      \"pmids\": [\"33621982\", \"33619090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"in-cell relevance of tandem-site tuning not shown\", \"structure of toxic tau-TIA-1 species undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved at residue resolution how PLD physicochemistry governs assembly and how ALS vs WDM mutations act oppositely—ALS mutations enhancing amyloid, WDM mutation attenuating stickiness.\",\n      \"evidence\": \"NMR, molecular dynamics, 3D electron crystallography, and aggregation assays of PLD with multiple disease mutations\",\n      \"pmids\": [\"36112647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"link to full-length cellular phase behavior partly indirect\", \"therapeutic targeting of PLD not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TIA-1's distinct activities—splice-site selection, translational silencing, and stress-granule/aggregate formation—are coordinated, compartment-resolved, and pharmacologically targetable in disease remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no integrated model coupling RNA binding stoichiometry to in-cell phase behavior\", \"phosphorylation/oxidation/zinc inputs not mapped to defined residues in vivo\", \"no demonstration that modulating TIA-1 phase transition rescues neurodegeneration in animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 10, 16, 18, 32, 33]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [3, 9, 10, 11, 37]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7, 28, 39]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [25, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 7, 10, 13, 28]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 19, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 9, 11, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 30, 36, 20]}\n    ],\n    \"complexes\": [\"stress granule\", \"U1 snRNP-associated spliceosomal complex\"],\n    \"partners\": [\"U1-C\", \"TIAL1\", \"TDP-43\", \"RSK2\", \"Sam68\", \"RBM39\", \"PCBP1\", \"MAPT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}