{"gene":"TIA1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1999,"finding":"TIA-1 acts downstream of eIF-2alpha phosphorylation to promote assembly of stress granules (SGs) harboring untranslated mRNAs. A phosphomimetic eIF-2alpha mutant (S51D) induces SG assembly, a nonphosphorylatable mutant (S51A) prevents it, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation.","method":"Transfection of phosphomimetic/nonphosphorylatable eIF-2alpha mutants in mammalian cells; dominant-negative TIA-1 truncation mutant; colocalization with poly(A)+ RNA","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic and cell biological approaches, foundational paper with >1000 citations","pmids":["10613902"],"is_preprint":false},{"year":2004,"finding":"Prion-like aggregation of TIA-1's glutamine-rich prion-related domain (PRD) mediates stress granule assembly. The PRD shows concentration-dependent aggregation inhibited by HSP70, resistance to protease digestion, and sequestration of HSP70/HSP27/HSP40. Substitution of the PRD with the yeast prion aggregation domain SUP35-NM reconstitutes SG assembly. TIA-1 knockout MEFs show impaired SG formation despite normal eIF2alpha phosphorylation.","method":"Truncation/domain-swap mutants, HSP70 overexpression, protease protection assay, TIA-1 knockout MEFs, live cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including domain reconstitution and knockout cells, replicated findings, >800 citations","pmids":["15371533"],"is_preprint":false},{"year":2000,"finding":"TIA-1 and PABP-I dynamically shuttle in and out of stress granules (FRAP analysis). Drugs that stabilize polysomes (emetine) inhibit SG assembly and dissolve preformed SGs, while drugs that destabilize polysomes (puromycin) promote SG assembly, demonstrating that SGs and polysomes exist in equilibrium. TIA-1ΔRRM transdominant inhibitor of SG assembly promotes expression of reporter genes, suggesting SGs regulate mRNA translation.","method":"FRAP of GFP-tagged TIA-1 and PABP-I in live cells; polysome-stabilizing/destabilizing drugs; reporter gene assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — live-cell FRAP with pharmacological perturbations and functional readout, >600 citations","pmids":["11121440"],"is_preprint":false},{"year":2000,"finding":"TIA-1 functions as a translational silencer of TNF-alpha mRNA by binding its AU-rich element (ARE) in the 3'UTR. TIA-1 knockout macrophages produce significantly more TNF-alpha protein without changes in transcript half-life, but with increased association of TNF-alpha mRNA with polysomes.","method":"Homologous recombination knockout mice; polysome fractionation; ELISA; mRNA half-life analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined molecular phenotype (polysome association), multiple readouts, >400 citations","pmids":["10921895"],"is_preprint":false},{"year":2000,"finding":"TIA-1 is an alternative pre-mRNA splicing regulator that binds U-rich sequences downstream of 5' splice sites to facilitate 5' splice site recognition by U1 snRNP. TIA-1 regulates splicing of Drosophila msl-2 and human Fas pre-mRNAs, and shows functional similarity to the S. cerevisiae splicing factor Nam8.","method":"In vitro splicing assays; UV cross-linking; specific immunoprecipitation; overexpression in cultured cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus cell-based overexpression, multiple targets validated, >250 citations","pmids":["11106748"],"is_preprint":false},{"year":1996,"finding":"RRM2 of TIA-1 is the domain that mediates specific binding to uridylate-rich RNA sequences, as determined by in vitro SELEX. RRM3 binds a broad population of cellular RNAs but not U-rich sequences selected by full-length protein; RRM1 has no detectable RNA-binding activity.","method":"In vitro selection/amplification (SELEX) 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 — in vitro biochemical dissection with domain mutants, Kd measurements, >190 citations","pmids":["8576255"],"is_preprint":false},{"year":2002,"finding":"TIA-1 directly interacts with U1 snRNP protein U1-C via its N-terminal region (RRM1 and Q-rich domain) to facilitate U1 snRNP recruitment to 5' splice sites. RRMs 2 and 3 are necessary and sufficient for pre-mRNA binding, while RRM1 and the Q domain are required for U1 snRNP association.","method":"Co-precipitation experiments; domain dissection; in vitro U1 snRNP recruitment assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct protein-protein interaction mapping with domain mutants and functional validation, >180 citations","pmids":["12486009"],"is_preprint":false},{"year":2000,"finding":"TIA-1 activates 5' splice site usage of the K-SAM alternative exon of FGF receptor 2 by binding to U-rich sequence IAS1 immediately downstream of the 5' splice site in a U1 snRNP-dependent manner. A TIA-1-MS2 coat protein fusion can substitute for wild-type TIA-1 when IAS1 is replaced by an MS2 operator near the 5' splice site.","method":"In vitro splicing assays; UV cross-linking/immunoprecipitation; overexpression in cultured cells; tethering assay with TIA-1-MS2 fusion","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro and in vivo splicing assays with tethering controls, >175 citations","pmids":["10938105"],"is_preprint":false},{"year":1995,"finding":"Fas-activated serine/threonine kinase (FAST) is rapidly activated upon Fas ligation and directly phosphorylates TIA-1. Phosphorylation of TIA-1 precedes DNA fragmentation during Fas-mediated apoptosis, placing FAST and TIA-1 in a signaling cascade upstream of apoptotic DNA fragmentation.","method":"Kinase activity assay; immunoprecipitation; phosphorylation time-course relative to DNA fragmentation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — direct in vitro kinase assay with temporal correlation to apoptotic outcome, >150 citations","pmids":["7544399"],"is_preprint":false},{"year":2003,"finding":"TIA-1 functions as a translational silencer of COX-2 by binding its ARE in the 3'UTR. TIA-1 null fibroblasts produce significantly more COX-2 protein without changes in COX-2 transcription or mRNA turnover. Colon cancer cells that overexpress COX-2 show defective TIA-1 binding to COX-2 mRNA in vitro and in vivo.","method":"RNA binding studies; TIA-1 null fibroblasts; Western blotting; RNA-binding IP; reporter assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with molecular phenotype, confirmed with in vitro and in vivo binding assays, >165 citations","pmids":["12885872"],"is_preprint":false},{"year":2005,"finding":"TIA-1 promotes Fas exon 6 inclusion by facilitating U1 snRNP binding to the exon 6 5' splice site, which in turn enhances U2AF binding to the upstream 3' splice site. PTB promotes exon skipping by binding an exonic splicing silencer and inhibiting U2AF and U2 snRNP recruitment. U1 snRNP recognition of the 5' splice site is required for both TIA-1-mediated U2AF enhancement and PTB-mediated U2AF inhibition.","method":"In vitro splicing assays; RNA-protein interaction studies; U1 snRNP/U2AF binding assays; functional reporters","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic in vitro reconstitution of splice site regulation, >290 citations","pmids":["16109372"],"is_preprint":false},{"year":2005,"finding":"TIA-1 immunoprecipitation followed by microarray analysis identified a U-rich, 30-37 nt bipartite RNA motif preferentially in 3'UTRs as the TIA-1 binding signature. TIA-1 binds ~3% of the UniGene transcripts. RNAi knockdown of TIA-1 revealed that TIA-1 represses translation of bound target mRNAs.","method":"RIP-Chip (immunoprecipitation of TIA-1-RNA complexes + microarray); biotinylated RNA pulldown/Western blot; RNA interference","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — systematic target identification with orthogonal validation and functional KD, >200 citations","pmids":["16227602"],"is_preprint":false},{"year":2006,"finding":"TIA-1 functions as a translational repressor of cytochrome c mRNA, opposing the translational activator HuR. Silencing TIA-1 dramatically increases cytochrome c translation, while silencing HuR reduces it. During ER stress, reduced HuR binding and altered TIA-1 activity contribute to decreased cytochrome c translation.","method":"RNA interference (siRNA knockdown); polysome fractionation; metabolic labeling of nascent protein; RIP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — RNAi with polysome fractionation and nascent protein synthesis measurements, >165 citations","pmids":["16581801"],"is_preprint":false},{"year":2006,"finding":"FAST kinase synergizes with TIA-1/TIAR to regulate Fas alternative splicing. FAST K depletion causes skipping of Fas exon 6; FAST K overexpression enhances exon 6 inclusion dependent on TIA-1/TIAR. In vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding.","method":"siRNA depletion; overexpression; in vitro splicing assays; in vitro kinase assay; U1 snRNP recruitment assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay combined with in vivo splicing perturbation and U1 snRNP recruitment assay","pmids":["17135269"],"is_preprint":false},{"year":2007,"finding":"TIA-1-mediated translational silencing promotes mRNA decay. Tethering TIA-1 to a reporter mRNA promotes its decay. TIA-1-mediated decay requires both 5'-3' (DCP2) and 3'-5' (exosome component Rrp46) decay pathways and is inhibited by drugs stabilizing polysomes (emetine, cycloheximide), indicating polysome disassembly is prerequisite.","method":"Gene array analysis; mRNA tethering assay; siRNA knockdown of decay pathway components; polysome-stabilizing drug treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — tethering assay combined with RNAi of specific decay factors and pharmacological dissection","pmids":["17711853"],"is_preprint":false},{"year":2008,"finding":"Systematic analysis showed TIA1/TIAL1 bind U-rich motifs within 100 nt downstream of 5' splice sites to regulate approximately 15% of alternative cassette exons. Simultaneous knockdown of TIA1 and TIAL1 increased skipping of 88% of alternatively spliced exons associated with U-rich motifs but did not affect 97% of exons lacking such motifs.","method":"Computational motif analysis; simultaneous siRNA knockdown of TIA1 and TIAL1; RT-PCR validation of 41 alternative exons","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 — systematic genome-wide analysis with targeted double KD and large-scale validation","pmids":["18456862"],"is_preprint":false},{"year":2008,"finding":"RSK2 kinase directly interacts with the prion-related domain of TIA-1 via its N-terminal kinase domain, co-localizing in stress granules. RSK2 and TIA-1 co-sequestration is codependent. Mitogen releases RSK2 from SGs for nuclear import in a TIA-1-dependent manner. Nuclear RSK2 promotes proliferation through cyclin D1 induction.","method":"Endogenous Co-IP; domain interaction mapping; siRNA silencing; live-cell imaging; nuclear fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — direct domain interaction mapping with functional readout, codependency established by reciprocal KD","pmids":["18775331"],"is_preprint":false},{"year":2011,"finding":"TIA-1 and TIAR are positive regulators of SMN2 exon 7 splicing in an intronic context where U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. Any single RRM in combination with the Q domain is necessary and sufficient for TIA1-dependent regulation. Increased TIA1 expression counteracts inhibitory effects of PTB on SMN exon 7 splicing.","method":"In vivo splicing assays with domain mutants; RNAi; epistasis with PTB","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain dissection in vivo combined with genetic epistasis with PTB","pmids":["21189287"],"is_preprint":false},{"year":2011,"finding":"TIA-1 and TIAR bind to the 5' end of 5'TOP mRNAs (encoding protein biosynthesis factors) under amino acid starvation, arresting their translation at the initiation step. This requires GCN2 kinase activation and mTOR pathway inactivation. Upon starvation, 5'TOP mRNAs are released from polysomes and accumulate in stress granules in a TIA-1/TIAR-dependent manner.","method":"PAR-CLIP/RIP; polysome profiling; stress granule colocalization; GCN2/mTOR pathway inhibition","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — direct RNA binding combined with polysome analysis and pathway epistasis, multiple orthogonal methods","pmids":["21979918"],"is_preprint":false},{"year":2014,"finding":"NMR, ITC, and SAXS structural analysis of TIA-1 revealed that 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 RNA binding induces a compact arrangement. RRM2,3 binds pyrimidine-rich FAS pre-mRNA or poly-U9 RNA with nanomolar affinity. RRM1 has little intrinsic RNA binding affinity.","method":"NMR solution structure; ITC; SAXS; RNA binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — multi-technique structural characterization with functional validation","pmids":["24682828"],"is_preprint":false},{"year":2016,"finding":"TIA-1 oxidation by reactive oxygen species (ROS/H2O2) inhibits stress granule assembly. When cells face both SG-inducing ER stress and oxidative stress simultaneously, oxidized TIA1 cannot nucleate SGs, promoting apoptosis. This mechanism is proposed to underlie neuronal cell death in neurodegenerative diseases.","method":"ROS treatment (H2O2); stress granule assembly assays; apoptosis measurements; TIA1 redox state analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct chemical perturbation of TIA1 oxidation state with defined SG assembly and apoptosis readouts","pmids":["26738979"],"is_preprint":false},{"year":2017,"finding":"ALS/FTD-associated mutations in the TIA1 low-complexity domain (e.g., P362L) significantly increase TIA1's propensity to undergo phase transition. In live cells, TIA1 LCD mutations delay stress granule disassembly, promote accumulation of non-dynamic SGs harboring TDP-43, and cause TDP-43 in SGs to become less mobile and insoluble.","method":"Genetics (mutation burden analysis); phase separation assays; FRAP in live cells; TDP-43 solubility fractionation; neuropathology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — human genetics combined with multiple cell biological assays and biophysical measurements, >500 citations","pmids":["28817800"],"is_preprint":false},{"year":2018,"finding":"PAR-CLIP of TIA1 and TIAL1 shows both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' and 3' splice sites. Double knockout of TIA1/TIAL1 increases target mRNA abundance and causes accumulation of aberrantly spliced mRNAs subject to NMD. Loss of PRKRA by mis-splicing triggers EIF2AK2/PKR activation and SG formation; ectopic PRKRA or EIF2AK2 knockout rescued this phenotype.","method":"PAR-CLIP; double knockout; transcriptomics; rescue by ectopic cDNA or second KO","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide binding data combined with DKO epistasis and rescue experiments","pmids":["29429924"],"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. Arsenite treatment of cells releases Zn2+ before stress granule formation, and TPEN inhibits TIA-1-positive SG formation. Zn2+ functions as a stress-inducible second messenger promoting TIA-1 multimerization and SG localization.","method":"In vitro phase separation assays with recombinant TIA-1; zinc chelation (TPEN); live-cell imaging; zinc release measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with recombinant protein combined with cell-based validation","pmids":["29298433"],"is_preprint":false},{"year":2005,"finding":"TIA-1 and TIAR continuously shuttle between cytoplasm and nucleus via distinct RRM-domain-mediated mechanisms. RRM2 and the first half of the auxiliary region mediate nuclear accumulation; RRM3 mediates nuclear export. Nuclear accumulation is Ran-GTP-dependent and transcription-dependent; nuclear export is independent of CRM1 and Ran-GTP.","method":"GFP-tagged domain mutants; nuclear/cytoplasmic fractionation; inhibitor treatments (transcription inhibitors, RanGTP depletion, leptomycin B); fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — systematic domain dissection with pharmacological pathway probes and functional localization readouts","pmids":["16278295"],"is_preprint":false},{"year":2016,"finding":"Tau interacts with TIA1 in brain tissue and the brain-protein interactome of TIA1 includes ribosomal proteins and other RBPs. Tau is required for normal TIA1-protein interactions. Tau expression accelerates stress granule formation, while TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in hippocampal neurons. TIA1 overexpression induces tau misfolding and neurodegeneration.","method":"Co-IP from brain tissue; TIA1 interactome (mass spectrometry); TIA1 KO/KD in cultured neurons; TIA1 overexpression; tau misfolding assays; neurotoxicity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP from tissue combined with KO/KD gain/loss-of-function with defined cellular phenotype","pmids":["27160897"],"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 (WNV 3'(-)SL RNA) via RRM2. The Kd for TIA-1 RRM2 interaction is 1.12 × 10^-7 M. WNV growth is reduced in TIAR knockout cells and reconstitution with TIAR rescues growth efficiency.","method":"RNA affinity purification; peptide sequencing; competition gel mobility-shift assays; recombinant domain binding assays; viral growth in KO cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical binding with domain mapping and Kd determination, functional validation in KO cells","pmids":["12414941"],"is_preprint":false},{"year":2013,"finding":"Welander distal myopathy (WDM) is caused by a dominant E384K mutation in the Q-rich domain of TIA1 (located in the region that interacts with U1-C splicing factor). Mutant TIA1 causes increased stress granule abundance and slower FRAP recovery in HeLa cells. WDM patient muscle shows focal TIA1 accumulation and increased splicing of SMN2 alternative exons.","method":"Linkage analysis; whole-genome/exome sequencing; FRAP; high-content SG quantification; RT-PCR splicing analysis; immunofluorescence of patient biopsies","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — human genetics converging with cell biology (FRAP) and splicing functional assays","pmids":["23401021"],"is_preprint":false},{"year":2007,"finding":"TIA-1 binds to AU-rich cis elements in COL2A1 intron 2 and modulates alternative splicing of exon 2. TIA-1 also interacts with the corresponding genomic DNA sequence (preferring single-stranded over double-stranded DNA), confirmed by ChIP assay. Active transcription by RNA polymerase disrupts TIA-1 DNA binding.","method":"Minigene splicing assay; RNP immunoprecipitation; chromatin immunoprecipitation (ChIP); competition binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding assays (RNA and DNA) with functional splicing readout, single lab","pmids":["17580305"],"is_preprint":false},{"year":2021,"finding":"TIA1 interaction with RNA and the combination of TIA1 + RNA is sufficient to drive phase separation of tau at physiological concentrations without crowding agents. Phase separation of tau in the presence of RNA and TIA1 generates tau oligomers that are significantly more toxic than tau aggregates generated by RNA alone or artificial crowding agents. Tau selectively copartitions with TIA1 but not G3BP1 under physiological conditions.","method":"In vitro phase separation assays with recombinant proteins; tau oligomer toxicity assays; selectivity comparison with other RBPs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant proteins, multiple orthogonal measures of phase separation and toxicity","pmids":["33619090"],"is_preprint":false},{"year":2022,"finding":"NMR, molecular dynamics simulations, and 3D electron crystallography revealed that ALS mutations P362L and A381T in TIA1's prion-like domain enhance self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively, increasing the likelihood of irreversible amyloid fibrillization. The WDM mutation E384K attenuates sticky properties. The dynamic structures of the PLD are synergistically determined by physicochemical properties of amino acids in units of five residues.","method":"NMR; 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 — multi-technique structural and computational analysis with biochemical validation of disease mutations","pmids":["36112647"],"is_preprint":false},{"year":2009,"finding":"Sam68 is recruited into stress granules under oxidative stress through direct complex formation with TIA-1. Sam68 domains aa269-321 and the KH domain are both essential for SG recruitment. Sam68 knockdown does not affect SG assembly, indicating it is not a core SG component but is recruited via TIA-1.","method":"Co-immunoprecipitation; domain mutants; siRNA knockdown; immunofluorescence colocalization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with domain mapping and KD, single lab","pmids":["19615357"],"is_preprint":false},{"year":2014,"finding":"TIA1 interacts with annexin A7 (ANXA7) as identified by yeast two-hybrid screening. ANXA7, acting as a GTPase, modulates TIA1 phosphorylation. Promoting ANXA7-TIA1 interaction inhibits TIA1 phosphorylation and promotes processing of pro-autophagic factor FLJ11812 and ATG13 expression in endothelial cells.","method":"Yeast two-hybrid; co-immunoprecipitation; pharmacological ANXA7 inhibitor (ABO); Western blotting","journal":"The international journal of biochemistry & cell biology","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid and co-IP without direct enzymatic validation of phosphorylation mechanism, single lab","pmids":["25461769"],"is_preprint":false},{"year":2011,"finding":"TDP-43 contributes to SG assembly and maintenance under oxidative stress, and differentially regulates TIA-1 and G3BP. Absence of TDP-43 disrupts controlled aggregation of TIA-1, slowing SG formation. Disease-associated TDP-43(R361S) is a loss-of-function mutation for SG formation and alters TIA-1 and G3BP levels.","method":"siRNA knockdown of TDP-43; TDP-43 disease mutant overexpression; immunofluorescence; Western blotting; SG quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — KD combined with disease mutants and quantitative SG phenotypes, multiple stressors tested","pmids":["21257637"],"is_preprint":false},{"year":2017,"finding":"TIA1 binds p53 mRNA in activated B lymphocytes and controls its translational silencing and stress granule localization. Upon DNA damage, TIA1 dissociates from p53 mRNA, which relocates from stress granules to polysomes for cap-independent translation. This is an ATM-dependent mechanism extended globally to key DNA damage response modulators.","method":"RIP; polysome fractionation; stress granule colocalization; ATM inhibition; global mRNA translation profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — RIP combined with polysome fractionation and ATM pathway epistasis, genome-wide translational profiling","pmids":["28904350"],"is_preprint":false},{"year":2021,"finding":"Full-length TIA-1 undergoes liquid-liquid phase separation in vitro induced by single-stranded RNA or DNA in a multisite, sequence-specific manner. Tandem binding sites (not single sites) are required to enhance TIA-1 phase separation, tuned by protein:binding site stoichiometry. Tandem TIA-1 binding sites in the p53 mRNA 3'UTR efficiently enhance TIA-1 phase separation, identifying them as potential SG nucleation sites.","method":"In vitro phase separation assays; fibril formation assays; SAXS; biotinylated RNA pulldown; designed and native RNA sequences","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple designed and native RNA sequences, biophysical characterization","pmids":["33621982"],"is_preprint":false},{"year":2022,"finding":"Intracellular tau accumulation inhibits autophagosome formation by binding the prion-related domain of TIA1 (PRD-TIA1), increasing intracellular amino acid levels, and activating mTORC1 signaling (increased p-4EBP1, p-p70S6K1, p-ULK1). Blocking tau-TIA1 interaction by overexpressing PRD-TIA1, TIA1 shRNA knockdown, or tau PROTAC degradation attenuates autophagy impairment.","method":"Co-immunoprecipitation; immunofluorescence; HPLC for amino acid measurement; mTORC1 activity assay; autophagosome formation (LC3 puncta/TEM); shRNA; overexpression; PROTAC","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP combined with multiple rescue approaches and pathway measurements, single lab","pmids":["35799293"],"is_preprint":false},{"year":2014,"finding":"TIA-1 RRM3 binds C-rich and U-rich RNA sequences with micromolar affinity (demonstrated by NMR STD and SPR). In combination with RRM2 and in full-length TIA-1, RRM3 significantly enhances binding to C-rich RNAs, consistent with its role in binding 5'TOP mRNA sequences.","method":"NMR saturation transfer difference (STD-NMR); surface plasmon resonance (SPR); biotinylated RNA pulldown","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1 — biophysical binding measurements (NMR+SPR) with domain-specific RRM3 characterization","pmids":["24824036"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of TIA-1 RRM2 in complex with DNA determined to 2.3 Å resolution, providing the first atomic resolution structure of any TIA protein RRM in complex with oligonucleotide. SAXS shows TIA-1 RRM23 adopts a compact structure upon complex formation with target RNA or DNA, with both RRMs engaging the 10-nt target sequence.","method":"X-ray crystallography (2.3 Å); SAXS; SPR binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — atomic resolution crystal structure with biophysical validation","pmids":["28184449"],"is_preprint":false}],"current_model":"TIA-1 is a multi-domain RNA-binding protein (three RRMs + Q-rich prion-like domain) that acts downstream of eIF2alpha phosphorylation to nucleate stress granules (SGs) via prion-like aggregation of its LCD—a process regulated by Zn2+, HSP70, ROS-mediated oxidation, and disease-associated mutations that alter liquid-to-solid phase transitions; TIA-1 also functions as a translational silencer of ARE-containing mRNAs (TNF-alpha, COX-2, cytochrome c, 5'TOP mRNAs) by sequestering them into SGs and rendering them susceptible to mRNA decay pathways, and as a splicing activator that binds U-rich intronic sequences downstream of 5' splice sites to recruit U1 snRNP (via direct interaction with U1-C through its RRM1 and Q domain) and thereby promote exon inclusion, with its activity further modulated by phosphorylation by FAST kinase, interaction with tau and RSK2, and nucleo-cytoplasmic shuttling controlled by distinct RRM domains."},"narrative":{"teleology":[{"year":1995,"claim":"Identifying TIA-1 as a substrate of FAST kinase during Fas-mediated apoptosis established that TIA-1 is post-translationally regulated in a signaling pathway upstream of DNA fragmentation.","evidence":"In vitro kinase assay and temporal phosphorylation analysis relative to apoptosis in Fas-stimulated cells","pmids":["7544399"],"confidence":"High","gaps":["Specific phosphorylation sites on TIA-1 not mapped","Functional consequence of phosphorylation on TIA-1 activity not determined"]},{"year":1996,"claim":"Determining that RRM2 provides sequence-specific recognition of U-rich RNA while RRM1 lacks detectable RNA binding resolved the division of labor among TIA-1's three RRM domains.","evidence":"SELEX with individual recombinant RRM domains and filter binding assays","pmids":["8576255"],"confidence":"High","gaps":["Role of RRM3 in RNA binding incompletely characterized","No structural information on binding mode"]},{"year":1999,"claim":"Demonstrating that TIA-1 acts downstream of eIF2α phosphorylation to nucleate stress granules containing untranslated mRNAs established TIA-1 as a core SG assembly factor linking translational arrest to cytoplasmic mRNP remodeling.","evidence":"Phosphomimetic and nonphosphorylatable eIF2α mutants combined with dominant-negative TIA-1 truncation in mammalian cells","pmids":["10613902"],"confidence":"High","gaps":["Mechanism by which eIF2α phosphorylation triggers TIA-1 recruitment unknown","Other SG nucleators not yet identified"]},{"year":2000,"claim":"Multiple studies converged to establish TIA-1 as both a translational silencer of ARE-containing mRNAs (TNF-α) and a splicing activator that promotes 5′ splice site recognition by U1 snRNP, revealing its dual nuclear/cytoplasmic regulatory functions.","evidence":"TIA-1 knockout macrophages showed increased TNF-α translation without mRNA destabilization; in vitro splicing assays and UV cross-linking showed TIA-1 binds U-rich intronic sequences to facilitate U1 snRNP recruitment on Fas, msl-2, and FGFR2 pre-mRNAs; FRAP showed dynamic TIA-1 shuttling in SGs","pmids":["10921895","11106748","10938105","11121440"],"confidence":"High","gaps":["Protein partner mediating U1 snRNP recruitment not identified","Whether translational silencing and splicing regulation share common RNA-binding surfaces unknown"]},{"year":2002,"claim":"Mapping the direct interaction between TIA-1 and U1 snRNP protein U1-C to RRM1 and the Q domain resolved how TIA-1 mechanistically bridges pre-mRNA binding (via RRM2/3) and spliceosome recruitment (via RRM1/Q).","evidence":"Co-precipitation and domain dissection with in vitro U1 snRNP recruitment assays","pmids":["12486009"],"confidence":"High","gaps":["Structural basis of TIA-1–U1-C interaction not determined","Whether phosphorylation modulates this interaction unknown"]},{"year":2004,"claim":"Demonstrating that TIA-1's prion-related domain drives concentration-dependent aggregation required for SG assembly — replaceable by yeast SUP35-NM — established the prion-like mechanism as the biophysical basis of SG nucleation.","evidence":"Domain-swap mutants, protease protection, HSP70 inhibition, and TIA-1 knockout MEFs showing impaired SG formation","pmids":["15371533"],"confidence":"High","gaps":["Whether PRD aggregation is liquid–liquid phase separation versus solid aggregation not distinguished","Endogenous regulators of PRD aggregation beyond HSP70 not identified"]},{"year":2005,"claim":"Genome-scale target identification and mechanistic dissection showed TIA-1 binds a bipartite U-rich motif in ~3% of transcripts to repress their translation, while in splicing it facilitates cross-exon communication by promoting U2AF recruitment through U1 snRNP positioning.","evidence":"RIP-Chip with RNAi validation for translational targets; in vitro reconstitution of Fas exon 6 splicing showing TIA-1-dependent U2AF enhancement; domain-mapped nucleo-cytoplasmic shuttling","pmids":["16227602","16109372","16278295"],"confidence":"High","gaps":["Overlap between splicing and translational target mRNAs not assessed","How shuttling dynamics partition TIA-1 between nuclear and cytoplasmic functions unclear"]},{"year":2007,"claim":"Establishing that TIA-1-mediated translational silencing channels mRNAs into both 5′→3′ (DCP2) and 3′→5′ (exosome) decay pathways connected SG-dependent translational arrest to mRNA turnover as a unified post-transcriptional regulatory axis.","evidence":"mRNA tethering assay with siRNA knockdown of DCP2 and Rrp46; polysome-stabilizing drug rescue","pmids":["17711853"],"confidence":"High","gaps":["Whether decay occurs within SGs or upon SG disassembly not resolved","Direct recruitment of decay factors by TIA-1 not shown"]},{"year":2006,"claim":"Demonstrating that FAST kinase phosphorylation of TIA-1 enhances U1 snRNP recruitment without increasing RNA binding provided the first evidence that a kinase tunes TIA-1's splicing activity through its protein-interaction rather than RNA-binding function.","evidence":"In vitro kinase assay combined with U1 snRNP recruitment and in vivo Fas splicing assays upon FAST knockdown or overexpression","pmids":["17135269"],"confidence":"High","gaps":["Specific phosphorylation sites mediating enhanced U1 recruitment not mapped","Structural mechanism of phosphorylation-enhanced U1-C interaction unknown"]},{"year":2008,"claim":"Systematic knockdown established that TIA1/TIAL1 regulate ~15% of alternative cassette exons genome-wide via U-rich motifs within 100 nt of 5′ splice sites, and RSK2 was identified as a signaling kinase that co-localizes with TIA-1 in SGs via direct PRD interaction.","evidence":"Double TIA1/TIAL1 siRNA knockdown with RT-PCR of 41 exons; endogenous co-IP and domain mapping for RSK2–TIA-1; live-cell imaging","pmids":["18456862","18775331"],"confidence":"High","gaps":["Whether RSK2 phosphorylates TIA-1 directly not demonstrated","Functional consequence of RSK2–TIA-1 interaction on splicing not tested"]},{"year":2011,"claim":"TIA-1/TIAR were shown to arrest translation of 5′TOP mRNAs under amino acid starvation via GCN2/mTOR signaling, extending TIA-1's translational silencing role beyond ARE-containing mRNAs to the global protein biosynthesis machinery.","evidence":"PAR-CLIP/RIP combined with polysome profiling and GCN2/mTOR pathway inhibition","pmids":["21979918"],"confidence":"High","gaps":["How TIA-1 recognizes 5′TOP sequences structurally not resolved","Whether TIA-1 directly senses amino acid levels or responds only via eIF2α phosphorylation unclear"]},{"year":2013,"claim":"Identification of the dominant E384K mutation in TIA1's Q-rich domain as the cause of Welander distal myopathy linked altered SG dynamics and splicing (SMN2) to a human Mendelian disease, validating the functional importance of the PRD in vivo.","evidence":"Linkage analysis and exome sequencing in WDM families; FRAP showing reduced SG dynamics; RT-PCR showing altered SMN2 splicing in patient muscle","pmids":["23401021"],"confidence":"High","gaps":["Whether E384K disrupts U1-C interaction not tested","Animal model of WDM not established"]},{"year":2014,"claim":"Structural studies by NMR, SAXS, and SPR resolved how TIA-1's RRMs are independent in solution but form a compact arrangement upon RNA binding, with RRM3 contributing C-rich RNA recognition relevant to 5′TOP mRNA binding.","evidence":"NMR solution structure, ITC, SAXS, SPR, and STD-NMR of individual and tandem RRM domains with various RNA substrates","pmids":["24682828","24824036"],"confidence":"High","gaps":["No high-resolution structure of full-length TIA-1 with RNA","PRD structure in context of full-length protein unknown"]},{"year":2016,"claim":"Two discoveries established that tau directly interacts with TIA1's PRD to promote SG formation and tau misfolding, while ROS-mediated oxidation of TIA-1 inhibits SG nucleation and promotes apoptosis, revealing opposing regulatory inputs on TIA-1 phase behavior with implications for neurodegeneration.","evidence":"Reciprocal co-IP from brain tissue with TIA1 KO/KD rescue for tau; H₂O₂ treatment with SG assembly and apoptosis readouts for ROS","pmids":["27160897","26738979"],"confidence":"High","gaps":["Oxidation sites on TIA-1 not mapped","Whether tau–TIA1 interaction occurs in liquid or solid phase in vivo unclear"]},{"year":2017,"claim":"ALS/FTD-associated mutations (P362L) in TIA1's LCD were shown to enhance phase transition propensity and delay SG disassembly, trapping TDP-43 in non-dynamic insoluble SGs, while crystal structure of RRM2–DNA complex provided the first atomic resolution view of TIA-1 target recognition.","evidence":"Phase separation assays and FRAP for disease mutations; X-ray crystallography at 2.3 Å for RRM2–DNA; SAXS for RRM23–RNA compact arrangement","pmids":["28817800","28184449"],"confidence":"High","gaps":["Whether SG persistence is sufficient to cause neurodegeneration in vivo not established","No structure of full RRM123–RNA complex"]},{"year":2018,"claim":"Zinc was identified as a stress-inducible second messenger promoting TIA-1 multimerization and phase separation, while PAR-CLIP of TIA1/TIAL1 double knockout revealed that loss of TIA1-dependent splicing triggers PKR activation and paradoxical SG formation through PRKRA mis-splicing.","evidence":"In vitro phase separation with recombinant TIA-1 ± Zn²⁺ and TPEN chelation in cells; PAR-CLIP with DKO transcriptomics and PRKRA/PKR rescue","pmids":["29298433","29429924"],"confidence":"High","gaps":["Zinc-binding sites on TIA-1 not mapped","Full catalog of splicing events whose mis-regulation has pathological consequences not complete"]},{"year":2021,"claim":"Reconstitution experiments showed that tandem TIA-1 binding sites in target RNAs (including p53 3′UTR) drive phase separation stoichiometrically, and that TIA1+RNA together generate toxic tau oligomers at physiological concentrations, mechanistically linking SG biology to tau toxicity.","evidence":"In vitro phase separation with designed and native RNA sequences; tau oligomer toxicity assays with recombinant TIA1/RNA/tau","pmids":["33621982","33619090"],"confidence":"High","gaps":["Whether tandem-site-driven phase separation occurs at endogenous TIA-1 concentrations in cells not demonstrated","In vivo relevance of TIA1-driven tau oligomerization to tauopathy progression not confirmed"]},{"year":2022,"claim":"Structural analysis of disease mutations in TIA1's PLD revealed that ALS mutations P362L and A381T enhance β-sheet formation and condensation respectively, while WDM mutation E384K attenuates self-assembly, providing a structural framework for genotype–phenotype correlations.","evidence":"NMR, molecular dynamics simulations, and 3D electron crystallography of PLD peptides","pmids":["36112647"],"confidence":"High","gaps":["Full-length PLD structure in phase-separated state not determined","Whether therapeutic modulation of PLD assembly is feasible unknown"]},{"year":null,"claim":"The structural basis of how TIA-1 simultaneously coordinates RNA binding, U1-C interaction, and prion-like self-assembly in the context of the full-length protein remains unresolved, as does the in vivo mechanism by which disease mutations in the PLD differentially drive myopathy versus ALS/FTD.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length TIA-1 structure in complex with RNA and protein partners","Animal models linking specific TIA1 mutations to neurodegenerative disease phenotypes are lacking","How cells distinguish reversible TIA-1 phase separation from pathological solidification is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,11,19,37,38]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,10,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,9,12,18,34]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[28,38]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,2,20,21,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,24]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,6,10,15,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,9,12,14,18,34]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,20,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,20]}],"complexes":["stress granules","U1 snRNP (via U1-C)"],"partners":["U1C","FASTK","TIAL1","MAPT","RPS6KA3","TDP43","KHDRBS1","ELAVL1"],"other_free_text":[]},"mechanistic_narrative":"TIA1 is a multifunctional RNA-binding protein that nucleates stress granules and regulates both mRNA translation and alternative pre-mRNA splicing. Its three RNA recognition motifs (RRMs) bind U-rich and C-rich RNA sequences — RRM2 provides primary sequence-specific recognition while RRM3 extends binding affinity and RRM1 mediates protein–protein interaction with U1 snRNP component U1-C — and its C-terminal glutamine-rich prion-related domain (PRD) drives concentration-dependent, prion-like self-aggregation required for stress granule nucleation downstream of eIF2α phosphorylation, a process regulated by Zn²⁺, HSP70, and oxidative modification [PMID:10613902, PMID:15371533, PMID:29298433, PMID:26738979]. As a translational silencer, TIA1 binds AU-rich elements in the 3′ UTRs of target mRNAs including TNF-α, COX-2, cytochrome c, p53, and 5′TOP transcripts, sequestering them from polysomes into stress granules and channeling them into both 5′→3′ and 3′→5′ mRNA decay pathways [PMID:10921895, PMID:12885872, PMID:16581801, PMID:21979918, PMID:17711853]. As a splicing activator, TIA1 binds U-rich intronic sequences downstream of 5′ splice sites and recruits U1 snRNP via direct interaction with U1-C through RRM1 and the Q domain, promoting exon inclusion of targets including Fas exon 6, FGFR2 K-SAM exon, and SMN2 exon 7, with its splicing activity enhanced by FAST kinase phosphorylation [PMID:11106748, PMID:12486009, PMID:16109372, PMID:17135269]. Mutations in TIA1's low-complexity domain cause Welander distal myopathy (E384K) and are associated with ALS/FTD (P362L), with disease mutations altering phase-separation dynamics and stress granule persistence, promoting pathological co-aggregation with TDP-43 and tau [PMID:23401021, PMID:28817800, PMID:36112647]."},"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 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A phosphomimetic eIF-2alpha mutant (S51D) induces SG assembly, a nonphosphorylatable mutant (S51A) prevents it, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation.\",\n      \"method\": \"Transfection of phosphomimetic/nonphosphorylatable eIF-2alpha mutants in mammalian cells; dominant-negative TIA-1 truncation mutant; colocalization with poly(A)+ RNA\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and cell biological approaches, foundational paper with >1000 citations\",\n      \"pmids\": [\"10613902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Prion-like aggregation of TIA-1's glutamine-rich prion-related domain (PRD) mediates stress granule assembly. The PRD shows concentration-dependent aggregation inhibited by HSP70, resistance to protease digestion, and sequestration of HSP70/HSP27/HSP40. Substitution of the PRD with the yeast prion aggregation domain SUP35-NM reconstitutes SG assembly. TIA-1 knockout MEFs show impaired SG formation despite normal eIF2alpha phosphorylation.\",\n      \"method\": \"Truncation/domain-swap mutants, HSP70 overexpression, protease protection assay, TIA-1 knockout MEFs, live cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including domain reconstitution and knockout cells, replicated findings, >800 citations\",\n      \"pmids\": [\"15371533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 and PABP-I dynamically shuttle in and out of stress granules (FRAP analysis). Drugs that stabilize polysomes (emetine) inhibit SG assembly and dissolve preformed SGs, while drugs that destabilize polysomes (puromycin) promote SG assembly, demonstrating that SGs and polysomes exist in equilibrium. TIA-1ΔRRM transdominant inhibitor of SG assembly promotes expression of reporter genes, suggesting SGs regulate mRNA translation.\",\n      \"method\": \"FRAP of GFP-tagged TIA-1 and PABP-I in live cells; polysome-stabilizing/destabilizing drugs; reporter gene assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live-cell FRAP with pharmacological perturbations and functional readout, >600 citations\",\n      \"pmids\": [\"11121440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 functions as a translational silencer of TNF-alpha mRNA by binding its AU-rich element (ARE) in the 3'UTR. TIA-1 knockout macrophages produce significantly more TNF-alpha protein without changes in transcript half-life, but with increased association of TNF-alpha mRNA with polysomes.\",\n      \"method\": \"Homologous recombination knockout mice; polysome fractionation; ELISA; mRNA half-life analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular phenotype (polysome association), multiple readouts, >400 citations\",\n      \"pmids\": [\"10921895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 is an alternative pre-mRNA splicing regulator that binds U-rich sequences downstream of 5' splice sites to facilitate 5' splice site recognition by U1 snRNP. TIA-1 regulates splicing of Drosophila msl-2 and human Fas pre-mRNAs, and shows functional similarity to the S. cerevisiae splicing factor Nam8.\",\n      \"method\": \"In vitro splicing assays; UV cross-linking; specific immunoprecipitation; overexpression in cultured cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus cell-based overexpression, multiple targets validated, >250 citations\",\n      \"pmids\": [\"11106748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RRM2 of TIA-1 is the domain that mediates specific binding to uridylate-rich RNA sequences, as determined by in vitro SELEX. RRM3 binds a broad population of cellular RNAs but not U-rich sequences selected by full-length protein; RRM1 has no detectable RNA-binding activity.\",\n      \"method\": \"In vitro selection/amplification (SELEX) 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 — in vitro biochemical dissection with domain mutants, Kd measurements, >190 citations\",\n      \"pmids\": [\"8576255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIA-1 directly interacts with U1 snRNP protein U1-C via its N-terminal region (RRM1 and Q-rich domain) to facilitate U1 snRNP recruitment to 5' splice sites. RRMs 2 and 3 are necessary and sufficient for pre-mRNA binding, while RRM1 and the Q domain are required for U1 snRNP association.\",\n      \"method\": \"Co-precipitation experiments; domain dissection; in vitro U1 snRNP recruitment assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-protein interaction mapping with domain mutants and functional validation, >180 citations\",\n      \"pmids\": [\"12486009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIA-1 activates 5' splice site usage of the K-SAM alternative exon of FGF receptor 2 by binding to U-rich sequence IAS1 immediately downstream of the 5' splice site in a U1 snRNP-dependent manner. A TIA-1-MS2 coat protein fusion can substitute for wild-type TIA-1 when IAS1 is replaced by an MS2 operator near the 5' splice site.\",\n      \"method\": \"In vitro splicing assays; UV cross-linking/immunoprecipitation; overexpression in cultured cells; tethering assay with TIA-1-MS2 fusion\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro and in vivo splicing assays with tethering controls, >175 citations\",\n      \"pmids\": [\"10938105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fas-activated serine/threonine kinase (FAST) is rapidly activated upon Fas ligation and directly phosphorylates TIA-1. Phosphorylation of TIA-1 precedes DNA fragmentation during Fas-mediated apoptosis, placing FAST and TIA-1 in a signaling cascade upstream of apoptotic DNA fragmentation.\",\n      \"method\": \"Kinase activity assay; immunoprecipitation; phosphorylation time-course relative to DNA fragmentation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro kinase assay with temporal correlation to apoptotic outcome, >150 citations\",\n      \"pmids\": [\"7544399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIA-1 functions as a translational silencer of COX-2 by binding its ARE in the 3'UTR. TIA-1 null fibroblasts produce significantly more COX-2 protein without changes in COX-2 transcription or mRNA turnover. Colon cancer cells that overexpress COX-2 show defective TIA-1 binding to COX-2 mRNA in vitro and in vivo.\",\n      \"method\": \"RNA binding studies; TIA-1 null fibroblasts; Western blotting; RNA-binding IP; reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with molecular phenotype, confirmed with in vitro and in vivo binding assays, >165 citations\",\n      \"pmids\": [\"12885872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 promotes Fas exon 6 inclusion by facilitating U1 snRNP binding to the exon 6 5' splice site, which in turn enhances U2AF binding to the upstream 3' splice site. PTB promotes exon skipping by binding an exonic splicing silencer and inhibiting U2AF and U2 snRNP recruitment. U1 snRNP recognition of the 5' splice site is required for both TIA-1-mediated U2AF enhancement and PTB-mediated U2AF inhibition.\",\n      \"method\": \"In vitro splicing assays; RNA-protein interaction studies; U1 snRNP/U2AF binding assays; functional reporters\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic in vitro reconstitution of splice site regulation, >290 citations\",\n      \"pmids\": [\"16109372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 immunoprecipitation followed by microarray analysis identified a U-rich, 30-37 nt bipartite RNA motif preferentially in 3'UTRs as the TIA-1 binding signature. TIA-1 binds ~3% of the UniGene transcripts. RNAi knockdown of TIA-1 revealed that TIA-1 represses translation of bound target mRNAs.\",\n      \"method\": \"RIP-Chip (immunoprecipitation of TIA-1-RNA complexes + microarray); biotinylated RNA pulldown/Western blot; RNA interference\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic target identification with orthogonal validation and functional KD, >200 citations\",\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, opposing the translational activator HuR. Silencing TIA-1 dramatically increases cytochrome c translation, while silencing HuR reduces it. During ER stress, reduced HuR binding and altered TIA-1 activity contribute to decreased cytochrome c translation.\",\n      \"method\": \"RNA interference (siRNA knockdown); polysome fractionation; metabolic labeling of nascent protein; RIP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with polysome fractionation and nascent protein synthesis measurements, >165 citations\",\n      \"pmids\": [\"16581801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FAST kinase synergizes with TIA-1/TIAR to regulate Fas alternative splicing. FAST K depletion causes skipping of Fas exon 6; FAST K overexpression enhances exon 6 inclusion dependent on TIA-1/TIAR. In vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding.\",\n      \"method\": \"siRNA depletion; overexpression; in vitro splicing assays; in vitro kinase assay; U1 snRNP recruitment assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay combined with in vivo splicing perturbation and U1 snRNP recruitment assay\",\n      \"pmids\": [\"17135269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIA-1-mediated translational silencing promotes mRNA decay. Tethering TIA-1 to a reporter mRNA promotes its decay. TIA-1-mediated decay requires both 5'-3' (DCP2) and 3'-5' (exosome component Rrp46) decay pathways and is inhibited by drugs stabilizing polysomes (emetine, cycloheximide), indicating polysome disassembly is prerequisite.\",\n      \"method\": \"Gene array analysis; mRNA tethering assay; siRNA knockdown of decay pathway components; polysome-stabilizing drug treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tethering assay combined with RNAi of specific decay factors and pharmacological dissection\",\n      \"pmids\": [\"17711853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Systematic analysis showed TIA1/TIAL1 bind U-rich motifs within 100 nt downstream of 5' splice sites to regulate approximately 15% of alternative cassette exons. Simultaneous knockdown of TIA1 and TIAL1 increased skipping of 88% of alternatively spliced exons associated with U-rich motifs but did not affect 97% of exons lacking such motifs.\",\n      \"method\": \"Computational motif analysis; simultaneous siRNA knockdown of TIA1 and TIAL1; RT-PCR validation of 41 alternative exons\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic genome-wide analysis with targeted double KD and large-scale validation\",\n      \"pmids\": [\"18456862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RSK2 kinase directly interacts with the prion-related domain of TIA-1 via its N-terminal kinase domain, co-localizing in stress granules. RSK2 and TIA-1 co-sequestration is codependent. Mitogen releases RSK2 from SGs for nuclear import in a TIA-1-dependent manner. Nuclear RSK2 promotes proliferation through cyclin D1 induction.\",\n      \"method\": \"Endogenous Co-IP; domain interaction mapping; siRNA silencing; live-cell imaging; nuclear fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct domain interaction mapping with functional readout, codependency established by reciprocal KD\",\n      \"pmids\": [\"18775331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIA-1 and TIAR are positive regulators of SMN2 exon 7 splicing in an intronic context where U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. Any single RRM in combination with the Q domain is necessary and sufficient for TIA1-dependent regulation. Increased TIA1 expression counteracts inhibitory effects of PTB on SMN exon 7 splicing.\",\n      \"method\": \"In vivo splicing assays with domain mutants; RNAi; epistasis with PTB\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain dissection in vivo combined with genetic epistasis with PTB\",\n      \"pmids\": [\"21189287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIA-1 and TIAR bind to the 5' end of 5'TOP mRNAs (encoding protein biosynthesis factors) under amino acid starvation, arresting their translation at the initiation step. This requires GCN2 kinase activation and mTOR pathway inactivation. Upon starvation, 5'TOP mRNAs are released from polysomes and accumulate in stress granules in a TIA-1/TIAR-dependent manner.\",\n      \"method\": \"PAR-CLIP/RIP; polysome profiling; stress granule colocalization; GCN2/mTOR pathway inhibition\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA binding combined with polysome analysis and pathway epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"21979918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR, ITC, and SAXS structural analysis of TIA-1 revealed that 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 RNA binding induces a compact arrangement. RRM2,3 binds pyrimidine-rich FAS pre-mRNA or poly-U9 RNA with nanomolar affinity. RRM1 has little intrinsic RNA binding affinity.\",\n      \"method\": \"NMR solution structure; ITC; SAXS; RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multi-technique structural characterization with functional validation\",\n      \"pmids\": [\"24682828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIA-1 oxidation by reactive oxygen species (ROS/H2O2) inhibits stress granule assembly. When cells face both SG-inducing ER stress and oxidative stress simultaneously, oxidized TIA1 cannot nucleate SGs, promoting apoptosis. This mechanism is proposed to underlie neuronal cell death in neurodegenerative diseases.\",\n      \"method\": \"ROS treatment (H2O2); stress granule assembly assays; apoptosis measurements; TIA1 redox state analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chemical perturbation of TIA1 oxidation state with defined SG assembly and apoptosis readouts\",\n      \"pmids\": [\"26738979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALS/FTD-associated mutations in the TIA1 low-complexity domain (e.g., P362L) significantly increase TIA1's propensity to undergo phase transition. In live cells, TIA1 LCD mutations delay stress granule disassembly, promote accumulation of non-dynamic SGs harboring TDP-43, and cause TDP-43 in SGs to become less mobile and insoluble.\",\n      \"method\": \"Genetics (mutation burden analysis); phase separation assays; FRAP in live cells; TDP-43 solubility fractionation; neuropathology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics combined with multiple cell biological assays and biophysical measurements, >500 citations\",\n      \"pmids\": [\"28817800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAR-CLIP of TIA1 and TIAL1 shows both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' and 3' splice sites. Double knockout of TIA1/TIAL1 increases target mRNA abundance and causes accumulation of aberrantly spliced mRNAs subject to NMD. Loss of PRKRA by mis-splicing triggers EIF2AK2/PKR activation and SG formation; ectopic PRKRA or EIF2AK2 knockout rescued this phenotype.\",\n      \"method\": \"PAR-CLIP; double knockout; transcriptomics; rescue by ectopic cDNA or second KO\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide binding data combined with DKO epistasis and rescue experiments\",\n      \"pmids\": [\"29429924\"],\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. Arsenite treatment of cells releases Zn2+ before stress granule formation, and TPEN inhibits TIA-1-positive SG formation. Zn2+ functions as a stress-inducible second messenger promoting TIA-1 multimerization and SG localization.\",\n      \"method\": \"In vitro phase separation assays with recombinant TIA-1; zinc chelation (TPEN); live-cell imaging; zinc release measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with recombinant protein combined with cell-based validation\",\n      \"pmids\": [\"29298433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIA-1 and TIAR continuously shuttle between cytoplasm and nucleus via distinct RRM-domain-mediated mechanisms. RRM2 and the first half of the auxiliary region mediate nuclear accumulation; RRM3 mediates nuclear export. Nuclear accumulation is Ran-GTP-dependent and transcription-dependent; nuclear export is independent of CRM1 and Ran-GTP.\",\n      \"method\": \"GFP-tagged domain mutants; nuclear/cytoplasmic fractionation; inhibitor treatments (transcription inhibitors, RanGTP depletion, leptomycin B); fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic domain dissection with pharmacological pathway probes and functional localization readouts\",\n      \"pmids\": [\"16278295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tau interacts with TIA1 in brain tissue and the brain-protein interactome of TIA1 includes ribosomal proteins and other RBPs. Tau is required for normal TIA1-protein interactions. Tau expression accelerates stress granule formation, while TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in hippocampal neurons. TIA1 overexpression induces tau misfolding and neurodegeneration.\",\n      \"method\": \"Co-IP from brain tissue; TIA1 interactome (mass spectrometry); TIA1 KO/KD in cultured neurons; TIA1 overexpression; tau misfolding assays; neurotoxicity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP from tissue combined with KO/KD gain/loss-of-function with defined cellular phenotype\",\n      \"pmids\": [\"27160897\"],\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 (WNV 3'(-)SL RNA) via RRM2. The Kd for TIA-1 RRM2 interaction is 1.12 × 10^-7 M. WNV growth is reduced in TIAR knockout cells and reconstitution with TIAR rescues growth efficiency.\",\n      \"method\": \"RNA affinity purification; peptide sequencing; competition gel mobility-shift assays; recombinant domain binding assays; viral growth in KO cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical binding with domain mapping and Kd determination, functional validation in KO cells\",\n      \"pmids\": [\"12414941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Welander distal myopathy (WDM) is caused by a dominant E384K mutation in the Q-rich domain of TIA1 (located in the region that interacts with U1-C splicing factor). Mutant TIA1 causes increased stress granule abundance and slower FRAP recovery in HeLa cells. WDM patient muscle shows focal TIA1 accumulation and increased splicing of SMN2 alternative exons.\",\n      \"method\": \"Linkage analysis; whole-genome/exome sequencing; FRAP; high-content SG quantification; RT-PCR splicing analysis; immunofluorescence of patient biopsies\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics converging with cell biology (FRAP) and splicing functional assays\",\n      \"pmids\": [\"23401021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIA-1 binds to AU-rich cis elements in COL2A1 intron 2 and modulates alternative splicing of exon 2. TIA-1 also interacts with the corresponding genomic DNA sequence (preferring single-stranded over double-stranded DNA), confirmed by ChIP assay. Active transcription by RNA polymerase disrupts TIA-1 DNA binding.\",\n      \"method\": \"Minigene splicing assay; RNP immunoprecipitation; chromatin immunoprecipitation (ChIP); competition binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays (RNA and DNA) with functional splicing readout, single lab\",\n      \"pmids\": [\"17580305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIA1 interaction with RNA and the combination of TIA1 + RNA is sufficient to drive phase separation of tau at physiological concentrations without crowding agents. Phase separation of tau in the presence of RNA and TIA1 generates tau oligomers that are significantly more toxic than tau aggregates generated by RNA alone or artificial crowding agents. Tau selectively copartitions with TIA1 but not G3BP1 under physiological conditions.\",\n      \"method\": \"In vitro phase separation assays with recombinant proteins; tau oligomer toxicity assays; selectivity comparison with other RBPs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant proteins, multiple orthogonal measures of phase separation and toxicity\",\n      \"pmids\": [\"33619090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NMR, molecular dynamics simulations, and 3D electron crystallography revealed that ALS mutations P362L and A381T in TIA1's prion-like domain enhance self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively, increasing the likelihood of irreversible amyloid fibrillization. The WDM mutation E384K attenuates sticky properties. The dynamic structures of the PLD are synergistically determined by physicochemical properties of amino acids in units of five residues.\",\n      \"method\": \"NMR; 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 — multi-technique structural and computational analysis with biochemical validation of disease mutations\",\n      \"pmids\": [\"36112647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 is recruited into stress granules under oxidative stress through direct complex formation with TIA-1. Sam68 domains aa269-321 and the KH domain are both essential for SG recruitment. Sam68 knockdown does not affect SG assembly, indicating it is not a core SG component but is recruited via TIA-1.\",\n      \"method\": \"Co-immunoprecipitation; domain mutants; siRNA knockdown; immunofluorescence colocalization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with domain mapping and KD, single lab\",\n      \"pmids\": [\"19615357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA1 interacts with annexin A7 (ANXA7) as identified by yeast two-hybrid screening. ANXA7, acting as a GTPase, modulates TIA1 phosphorylation. Promoting ANXA7-TIA1 interaction inhibits TIA1 phosphorylation and promotes processing of pro-autophagic factor FLJ11812 and ATG13 expression in endothelial cells.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; pharmacological ANXA7 inhibitor (ABO); Western blotting\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and co-IP without direct enzymatic validation of phosphorylation mechanism, single lab\",\n      \"pmids\": [\"25461769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TDP-43 contributes to SG assembly and maintenance under oxidative stress, and differentially regulates TIA-1 and G3BP. Absence of TDP-43 disrupts controlled aggregation of TIA-1, slowing SG formation. Disease-associated TDP-43(R361S) is a loss-of-function mutation for SG formation and alters TIA-1 and G3BP levels.\",\n      \"method\": \"siRNA knockdown of TDP-43; TDP-43 disease mutant overexpression; immunofluorescence; Western blotting; SG quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD combined with disease mutants and quantitative SG phenotypes, multiple stressors tested\",\n      \"pmids\": [\"21257637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIA1 binds p53 mRNA in activated B lymphocytes and controls its translational silencing and stress granule localization. Upon DNA damage, TIA1 dissociates from p53 mRNA, which relocates from stress granules to polysomes for cap-independent translation. This is an ATM-dependent mechanism extended globally to key DNA damage response modulators.\",\n      \"method\": \"RIP; polysome fractionation; stress granule colocalization; ATM inhibition; global mRNA translation profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP combined with polysome fractionation and ATM pathway epistasis, genome-wide translational profiling\",\n      \"pmids\": [\"28904350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Full-length TIA-1 undergoes liquid-liquid phase separation in vitro induced by single-stranded RNA or DNA in a multisite, sequence-specific manner. Tandem binding sites (not single sites) are required to enhance TIA-1 phase separation, tuned by protein:binding site stoichiometry. Tandem TIA-1 binding sites in the p53 mRNA 3'UTR efficiently enhance TIA-1 phase separation, identifying them as potential SG nucleation sites.\",\n      \"method\": \"In vitro phase separation assays; fibril formation assays; SAXS; biotinylated RNA pulldown; designed and native RNA sequences\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple designed and native RNA sequences, biophysical characterization\",\n      \"pmids\": [\"33621982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intracellular tau accumulation inhibits autophagosome formation by binding the prion-related domain of TIA1 (PRD-TIA1), increasing intracellular amino acid levels, and activating mTORC1 signaling (increased p-4EBP1, p-p70S6K1, p-ULK1). Blocking tau-TIA1 interaction by overexpressing PRD-TIA1, TIA1 shRNA knockdown, or tau PROTAC degradation attenuates autophagy impairment.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; HPLC for amino acid measurement; mTORC1 activity assay; autophagosome formation (LC3 puncta/TEM); shRNA; overexpression; PROTAC\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP combined with multiple rescue approaches and pathway measurements, single lab\",\n      \"pmids\": [\"35799293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIA-1 RRM3 binds C-rich and U-rich RNA sequences with micromolar affinity (demonstrated by NMR STD and SPR). In combination with RRM2 and in full-length TIA-1, RRM3 significantly enhances binding to C-rich RNAs, consistent with its role in binding 5'TOP mRNA sequences.\",\n      \"method\": \"NMR saturation transfer difference (STD-NMR); surface plasmon resonance (SPR); biotinylated RNA pulldown\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biophysical binding measurements (NMR+SPR) with domain-specific RRM3 characterization\",\n      \"pmids\": [\"24824036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of TIA-1 RRM2 in complex with DNA determined to 2.3 Å resolution, providing the first atomic resolution structure of any TIA protein RRM in complex with oligonucleotide. SAXS shows TIA-1 RRM23 adopts a compact structure upon complex formation with target RNA or DNA, with both RRMs engaging the 10-nt target sequence.\",\n      \"method\": \"X-ray crystallography (2.3 Å); SAXS; SPR binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic resolution crystal structure with biophysical validation\",\n      \"pmids\": [\"28184449\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIA-1 is a multi-domain RNA-binding protein (three RRMs + Q-rich prion-like domain) that acts downstream of eIF2alpha phosphorylation to nucleate stress granules (SGs) via prion-like aggregation of its LCD—a process regulated by Zn2+, HSP70, ROS-mediated oxidation, and disease-associated mutations that alter liquid-to-solid phase transitions; TIA-1 also functions as a translational silencer of ARE-containing mRNAs (TNF-alpha, COX-2, cytochrome c, 5'TOP mRNAs) by sequestering them into SGs and rendering them susceptible to mRNA decay pathways, and as a splicing activator that binds U-rich intronic sequences downstream of 5' splice sites to recruit U1 snRNP (via direct interaction with U1-C through its RRM1 and Q domain) and thereby promote exon inclusion, with its activity further modulated by phosphorylation by FAST kinase, interaction with tau and RSK2, and nucleo-cytoplasmic shuttling controlled by distinct RRM domains.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TIA1 is a multifunctional RNA-binding protein that nucleates stress granules and regulates both mRNA translation and alternative pre-mRNA splicing. Its three RNA recognition motifs (RRMs) bind U-rich and C-rich RNA sequences — RRM2 provides primary sequence-specific recognition while RRM3 extends binding affinity and RRM1 mediates protein–protein interaction with U1 snRNP component U1-C — and its C-terminal glutamine-rich prion-related domain (PRD) drives concentration-dependent, prion-like self-aggregation required for stress granule nucleation downstream of eIF2α phosphorylation, a process regulated by Zn²⁺, HSP70, and oxidative modification [PMID:10613902, PMID:15371533, PMID:29298433, PMID:26738979]. As a translational silencer, TIA1 binds AU-rich elements in the 3′ UTRs of target mRNAs including TNF-α, COX-2, cytochrome c, p53, and 5′TOP transcripts, sequestering them from polysomes into stress granules and channeling them into both 5′→3′ and 3′→5′ mRNA decay pathways [PMID:10921895, PMID:12885872, PMID:16581801, PMID:21979918, PMID:17711853]. As a splicing activator, TIA1 binds U-rich intronic sequences downstream of 5′ splice sites and recruits U1 snRNP via direct interaction with U1-C through RRM1 and the Q domain, promoting exon inclusion of targets including Fas exon 6, FGFR2 K-SAM exon, and SMN2 exon 7, with its splicing activity enhanced by FAST kinase phosphorylation [PMID:11106748, PMID:12486009, PMID:16109372, PMID:17135269]. Mutations in TIA1's low-complexity domain cause Welander distal myopathy (E384K) and are associated with ALS/FTD (P362L), with disease mutations altering phase-separation dynamics and stress granule persistence, promoting pathological co-aggregation with TDP-43 and tau [PMID:23401021, PMID:28817800, PMID:36112647].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying TIA-1 as a substrate of FAST kinase during Fas-mediated apoptosis established that TIA-1 is post-translationally regulated in a signaling pathway upstream of DNA fragmentation.\",\n      \"evidence\": \"In vitro kinase assay and temporal phosphorylation analysis relative to apoptosis in Fas-stimulated cells\",\n      \"pmids\": [\"7544399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites on TIA-1 not mapped\", \"Functional consequence of phosphorylation on TIA-1 activity not determined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Determining that RRM2 provides sequence-specific recognition of U-rich RNA while RRM1 lacks detectable RNA binding resolved the division of labor among TIA-1's three RRM domains.\",\n      \"evidence\": \"SELEX with individual recombinant RRM domains and filter binding assays\",\n      \"pmids\": [\"8576255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of RRM3 in RNA binding incompletely characterized\", \"No structural information on binding mode\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that TIA-1 acts downstream of eIF2α phosphorylation to nucleate stress granules containing untranslated mRNAs established TIA-1 as a core SG assembly factor linking translational arrest to cytoplasmic mRNP remodeling.\",\n      \"evidence\": \"Phosphomimetic and nonphosphorylatable eIF2α mutants combined with dominant-negative TIA-1 truncation in mammalian cells\",\n      \"pmids\": [\"10613902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which eIF2α phosphorylation triggers TIA-1 recruitment unknown\", \"Other SG nucleators not yet identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Multiple studies converged to establish TIA-1 as both a translational silencer of ARE-containing mRNAs (TNF-α) and a splicing activator that promotes 5′ splice site recognition by U1 snRNP, revealing its dual nuclear/cytoplasmic regulatory functions.\",\n      \"evidence\": \"TIA-1 knockout macrophages showed increased TNF-α translation without mRNA destabilization; in vitro splicing assays and UV cross-linking showed TIA-1 binds U-rich intronic sequences to facilitate U1 snRNP recruitment on Fas, msl-2, and FGFR2 pre-mRNAs; FRAP showed dynamic TIA-1 shuttling in SGs\",\n      \"pmids\": [\"10921895\", \"11106748\", \"10938105\", \"11121440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein partner mediating U1 snRNP recruitment not identified\", \"Whether translational silencing and splicing regulation share common RNA-binding surfaces unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping the direct interaction between TIA-1 and U1 snRNP protein U1-C to RRM1 and the Q domain resolved how TIA-1 mechanistically bridges pre-mRNA binding (via RRM2/3) and spliceosome recruitment (via RRM1/Q).\",\n      \"evidence\": \"Co-precipitation and domain dissection with in vitro U1 snRNP recruitment assays\",\n      \"pmids\": [\"12486009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TIA-1–U1-C interaction not determined\", \"Whether phosphorylation modulates this interaction unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that TIA-1's prion-related domain drives concentration-dependent aggregation required for SG assembly — replaceable by yeast SUP35-NM — established the prion-like mechanism as the biophysical basis of SG nucleation.\",\n      \"evidence\": \"Domain-swap mutants, protease protection, HSP70 inhibition, and TIA-1 knockout MEFs showing impaired SG formation\",\n      \"pmids\": [\"15371533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRD aggregation is liquid–liquid phase separation versus solid aggregation not distinguished\", \"Endogenous regulators of PRD aggregation beyond HSP70 not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genome-scale target identification and mechanistic dissection showed TIA-1 binds a bipartite U-rich motif in ~3% of transcripts to repress their translation, while in splicing it facilitates cross-exon communication by promoting U2AF recruitment through U1 snRNP positioning.\",\n      \"evidence\": \"RIP-Chip with RNAi validation for translational targets; in vitro reconstitution of Fas exon 6 splicing showing TIA-1-dependent U2AF enhancement; domain-mapped nucleo-cytoplasmic shuttling\",\n      \"pmids\": [\"16227602\", \"16109372\", \"16278295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overlap between splicing and translational target mRNAs not assessed\", \"How shuttling dynamics partition TIA-1 between nuclear and cytoplasmic functions unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that TIA-1-mediated translational silencing channels mRNAs into both 5′→3′ (DCP2) and 3′→5′ (exosome) decay pathways connected SG-dependent translational arrest to mRNA turnover as a unified post-transcriptional regulatory axis.\",\n      \"evidence\": \"mRNA tethering assay with siRNA knockdown of DCP2 and Rrp46; polysome-stabilizing drug rescue\",\n      \"pmids\": [\"17711853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether decay occurs within SGs or upon SG disassembly not resolved\", \"Direct recruitment of decay factors by TIA-1 not shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that FAST kinase phosphorylation of TIA-1 enhances U1 snRNP recruitment without increasing RNA binding provided the first evidence that a kinase tunes TIA-1's splicing activity through its protein-interaction rather than RNA-binding function.\",\n      \"evidence\": \"In vitro kinase assay combined with U1 snRNP recruitment and in vivo Fas splicing assays upon FAST knockdown or overexpression\",\n      \"pmids\": [\"17135269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites mediating enhanced U1 recruitment not mapped\", \"Structural mechanism of phosphorylation-enhanced U1-C interaction unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Systematic knockdown established that TIA1/TIAL1 regulate ~15% of alternative cassette exons genome-wide via U-rich motifs within 100 nt of 5′ splice sites, and RSK2 was identified as a signaling kinase that co-localizes with TIA-1 in SGs via direct PRD interaction.\",\n      \"evidence\": \"Double TIA1/TIAL1 siRNA knockdown with RT-PCR of 41 exons; endogenous co-IP and domain mapping for RSK2–TIA-1; live-cell imaging\",\n      \"pmids\": [\"18456862\", \"18775331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RSK2 phosphorylates TIA-1 directly not demonstrated\", \"Functional consequence of RSK2–TIA-1 interaction on splicing not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"TIA-1/TIAR were shown to arrest translation of 5′TOP mRNAs under amino acid starvation via GCN2/mTOR signaling, extending TIA-1's translational silencing role beyond ARE-containing mRNAs to the global protein biosynthesis machinery.\",\n      \"evidence\": \"PAR-CLIP/RIP combined with polysome profiling and GCN2/mTOR pathway inhibition\",\n      \"pmids\": [\"21979918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIA-1 recognizes 5′TOP sequences structurally not resolved\", \"Whether TIA-1 directly senses amino acid levels or responds only via eIF2α phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of the dominant E384K mutation in TIA1's Q-rich domain as the cause of Welander distal myopathy linked altered SG dynamics and splicing (SMN2) to a human Mendelian disease, validating the functional importance of the PRD in vivo.\",\n      \"evidence\": \"Linkage analysis and exome sequencing in WDM families; FRAP showing reduced SG dynamics; RT-PCR showing altered SMN2 splicing in patient muscle\",\n      \"pmids\": [\"23401021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E384K disrupts U1-C interaction not tested\", \"Animal model of WDM not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural studies by NMR, SAXS, and SPR resolved how TIA-1's RRMs are independent in solution but form a compact arrangement upon RNA binding, with RRM3 contributing C-rich RNA recognition relevant to 5′TOP mRNA binding.\",\n      \"evidence\": \"NMR solution structure, ITC, SAXS, SPR, and STD-NMR of individual and tandem RRM domains with various RNA substrates\",\n      \"pmids\": [\"24682828\", \"24824036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length TIA-1 with RNA\", \"PRD structure in context of full-length protein unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two discoveries established that tau directly interacts with TIA1's PRD to promote SG formation and tau misfolding, while ROS-mediated oxidation of TIA-1 inhibits SG nucleation and promotes apoptosis, revealing opposing regulatory inputs on TIA-1 phase behavior with implications for neurodegeneration.\",\n      \"evidence\": \"Reciprocal co-IP from brain tissue with TIA1 KO/KD rescue for tau; H₂O₂ treatment with SG assembly and apoptosis readouts for ROS\",\n      \"pmids\": [\"27160897\", \"26738979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oxidation sites on TIA-1 not mapped\", \"Whether tau–TIA1 interaction occurs in liquid or solid phase in vivo unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ALS/FTD-associated mutations (P362L) in TIA1's LCD were shown to enhance phase transition propensity and delay SG disassembly, trapping TDP-43 in non-dynamic insoluble SGs, while crystal structure of RRM2–DNA complex provided the first atomic resolution view of TIA-1 target recognition.\",\n      \"evidence\": \"Phase separation assays and FRAP for disease mutations; X-ray crystallography at 2.3 Å for RRM2–DNA; SAXS for RRM23–RNA compact arrangement\",\n      \"pmids\": [\"28817800\", \"28184449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SG persistence is sufficient to cause neurodegeneration in vivo not established\", \"No structure of full RRM123–RNA complex\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Zinc was identified as a stress-inducible second messenger promoting TIA-1 multimerization and phase separation, while PAR-CLIP of TIA1/TIAL1 double knockout revealed that loss of TIA1-dependent splicing triggers PKR activation and paradoxical SG formation through PRKRA mis-splicing.\",\n      \"evidence\": \"In vitro phase separation with recombinant TIA-1 ± Zn²⁺ and TPEN chelation in cells; PAR-CLIP with DKO transcriptomics and PRKRA/PKR rescue\",\n      \"pmids\": [\"29298433\", \"29429924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Zinc-binding sites on TIA-1 not mapped\", \"Full catalog of splicing events whose mis-regulation has pathological consequences not complete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution experiments showed that tandem TIA-1 binding sites in target RNAs (including p53 3′UTR) drive phase separation stoichiometrically, and that TIA1+RNA together generate toxic tau oligomers at physiological concentrations, mechanistically linking SG biology to tau toxicity.\",\n      \"evidence\": \"In vitro phase separation with designed and native RNA sequences; tau oligomer toxicity assays with recombinant TIA1/RNA/tau\",\n      \"pmids\": [\"33621982\", \"33619090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tandem-site-driven phase separation occurs at endogenous TIA-1 concentrations in cells not demonstrated\", \"In vivo relevance of TIA1-driven tau oligomerization to tauopathy progression not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural analysis of disease mutations in TIA1's PLD revealed that ALS mutations P362L and A381T enhance β-sheet formation and condensation respectively, while WDM mutation E384K attenuates self-assembly, providing a structural framework for genotype–phenotype correlations.\",\n      \"evidence\": \"NMR, molecular dynamics simulations, and 3D electron crystallography of PLD peptides\",\n      \"pmids\": [\"36112647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length PLD structure in phase-separated state not determined\", \"Whether therapeutic modulation of PLD assembly is feasible unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of how TIA-1 simultaneously coordinates RNA binding, U1-C interaction, and prion-like self-assembly in the context of the full-length protein remains unresolved, as does the in vivo mechanism by which disease mutations in the PLD differentially drive myopathy versus ALS/FTD.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length TIA-1 structure in complex with RNA and protein partners\", \"Animal models linking specific TIA1 mutations to neurodegenerative disease phenotypes are lacking\", \"How cells distinguish reversible TIA-1 phase separation from pathological solidification is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 11, 19, 37, 38]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 10, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 9, 12, 18, 34]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [28, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 2, 20, 21, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 6, 10, 15, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 9, 12, 14, 18, 34]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 20, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 20]}\n    ],\n    \"complexes\": [\n      \"stress granules\",\n      \"U1 snRNP (via U1-C)\"\n    ],\n    \"partners\": [\n      \"U1C\",\n      \"FASTK\",\n      \"TIAL1\",\n      \"MAPT\",\n      \"RPS6KA3\",\n      \"TDP43\",\n      \"KHDRBS1\",\n      \"ELAVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}