{"gene":"TIAL1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1999,"finding":"TIAR (and TIA-1) colocalize with poly(A)+ RNA at cytoplasmic stress granules; stress granule assembly is initiated downstream of eIF-2alpha phosphorylation at S51, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of stress granule formation, placing TIAR/TIA-1 downstream of eIF-2alpha phosphorylation in the stress-induced translational arrest pathway.","method":"Fluorescence microscopy, phosphomimetic (S51D) and nonphosphorylatable (S51A) eIF-2alpha mutant transfection, dominant-negative TIA-1 mutant transfection","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with phosphomimetic mutants plus dominant-negative approach, replicated across multiple stress conditions in single rigorous study","pmids":["10613902"],"is_preprint":false},{"year":1999,"finding":"TIAR binds to the AU-rich element (ARE) of TNF-alpha mRNA (complex 1 requiring clustered AUUUA pentamers) in the cytoplasm of macrophages, implicating TIAR in post-transcriptional regulation of TNF-alpha translation.","method":"RNA electrophoretic mobility shift assay (EMSA), protein identification by immunoprecipitation, cytoplasmic localization by fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, EMSA and immunoprecipitation, two orthogonal methods identifying TIAR in complex","pmids":["9890998"],"is_preprint":false},{"year":1996,"finding":"RRM2 of both TIA-1 and TIAR is the primary domain mediating specific binding to uridylate-rich RNA sequences; RRM1 does not bind RNA due to negatively charged residues in the RNP1 octamer; RRM3 binds a broad population of cellular RNAs but not uridylate-rich sequences selected by full-length protein. Affinity for selected RNA increases when RRM2 is expressed with RRM1 and RRM3 (Kd ~20 nM) vs. RRM2 alone (Kd ~50 nM).","method":"In vitro selection/amplification (SELEX) from random RNA pools, filter binding assays, domain deletion/mutant expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with domain mutagenesis and quantitative binding assays in single rigorous study","pmids":["8576255"],"is_preprint":false},{"year":2011,"finding":"Upon amino acid starvation, TIA-1 and TIAR assemble onto the 5' ends of 5'TOP mRNAs and arrest translation at the initiation step, causing polysome release and accumulation of 5'TOP mRNAs in stress granules; this requires GCN2 kinase activation and mTOR pathway inactivation.","method":"RNA immunoprecipitation, polysome profiling, siRNA knockdown, luciferase reporter assays, stress granule imaging","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, polysome profiling, genetic knockdown, reporters) in single study demonstrating translational repression mechanism","pmids":["21979918"],"is_preprint":false},{"year":1998,"finding":"TIAR is essential for primordial germ cell (PGC) survival; TIAR-deficient mice fail to develop spermatogonia or oogonia due to reduced PGC survival after migration to the genital ridge by E11.5, with complete PGC absence by E13.5. TIAR-deficient embryonic stem cells also fail to proliferate without exogenous LIF in methylcellulose culture.","method":"TIAR knockout mouse generation, embryo histology, timed developmental analysis, in vitro methylcellulose colony assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined developmental phenotype and two orthogonal readouts (in vivo PGC counting, in vitro ES cell proliferation)","pmids":["9482885"],"is_preprint":false},{"year":2002,"finding":"TIAR (p42) specifically binds the 3' terminal stem-loop of West Nile virus minus-strand RNA (WNV 3'(-)SL RNA) via RRM2 with Kd ~15 nM; TIA-1 also binds but with ~7-fold lower affinity (Kd ~112 nM). WNV replication is less efficient in TIAR knockout cells, and reconstitution with TIAR partially restores WNV growth, indicating a functional role for TIAR in WNV replication.","method":"RNA affinity column purification, peptide sequencing, UV cross-linking/immunoprecipitation, competition gel mobility shift assay, recombinant protein binding, TIAR knockout cell lines with virus growth assay and reconstitution","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical binding mapped to specific domain with Kd measurement plus functional reconstitution in knockout cells","pmids":["12414941"],"is_preprint":false},{"year":2007,"finding":"AUF1 and TIAR compete for binding to the ARE of MYC mRNA; TIAR acts as a translational suppressor of MYC, and cell proliferation levels are inversely proportional to TIAR abundance. Altering association of one ARE-binding protein with MYC mRNA reciprocally affects the other's association; genetic experiments show AUF1 and TIAR control proliferation through a MYC-dependent pathway.","method":"RNA immunoprecipitation, reporter assays, siRNA knockdown/overexpression, cell proliferation assays, mRNA abundance measurements","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, reporters, genetic epistasis) in single rigorous study demonstrating competitive translational repression mechanism","pmids":["17486099"],"is_preprint":false},{"year":2006,"finding":"TIAR selectively binds the 3'UTRs of mRNAs encoding translation factors (eIF4A, eIF4E, eEF1B) and c-Myc and potently suppresses their translation, particularly in response to UVC irradiation; siRNA silencing of TIAR significantly relieves UVC-induced global translational inhibition.","method":"RNA immunoprecipitation, reporter assays, siRNA knockdown, polysome profiling, UV irradiation stress assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP, functional reporters, and siRNA rescue with multiple target mRNAs validated in single study","pmids":["16537914"],"is_preprint":false},{"year":1995,"finding":"TIAR is concentrated in the nucleus of hematopoietic and nonhematopoietic cells under normal conditions, but translocates from nucleus to cytoplasm within 30 min of Fas ligation during apoptosis, preceding the onset of DNA fragmentation; this redistribution is specific to apoptosis and not observed during mitogen-induced activation.","method":"Immunofluorescence, subcellular fractionation, Western blot, Fas-mediated apoptosis induction, time-course analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence (precedes DNA fragmentation), two orthogonal methods, specific to apoptotic stimulus","pmids":["7533298"],"is_preprint":false},{"year":2001,"finding":"TIAR activates splicing of alternative exons with weak 5' splice sites followed by U-rich stretches, including autoregulatory exons on the TIAR and TIA-1 pre-mRNAs; TIA-1 directly activates TIAR alternative exon 5' splice sites in vitro requiring a downstream U-rich stretch of at least 10 residues. TIAR overexpression induces use of cryptic 5' splice sites that are also followed by U-rich sequences when the native U-rich stretch is deleted.","method":"Overexpression in cells, in vitro splicing assays, minigene reporters, deletion mutagenesis of U-rich sequences","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro splicing reconstitution with mutagenesis establishing U-rich sequence requirement, supported by cell-based overexpression data","pmids":["11514562"],"is_preprint":false},{"year":2008,"finding":"TIA1 and TIAL1 regulate inclusion of ~15% of alternative cassette exons genome-wide via U-rich intronic motifs downstream of 5' splice sites; simultaneous knockdown of TIA1 and TIAL1 caused skipping of 88% of alternatively spliced exons associated with U-rich motifs but did not affect 97% of exons lacking such motifs; exon skipping correlated with proximity and U-richness of adjacent intronic region.","method":"Simultaneous siRNA knockdown of TIA1 and TIAL1, splicing-sensitive microarray, RT-PCR validation, bioinformatic motif analysis","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale functional screen with validated double knockdown and multiple RT-PCR confirmations across many targets","pmids":["18456862"],"is_preprint":false},{"year":2003,"finding":"TIAR binds to a U-tract sequence motif downstream of a pseudo 5' splice site within the calcitonin/CGRP intron enhancer and promotes inclusion of the alternative 3'-terminal exon >200 nt upstream; TIAR's binding depends on U1 and U6 snRNA interactions with the pseudo 5' splice site, and TIAR binding in turn promotes U6 snRNA binding (synergistic relationship).","method":"UV cross-linking, EMSA, dominant-negative TIAR mutant overexpression, minigene reporter assays, snRNA interaction analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple methods (UV cross-linking, dominant-negative, reporters) establishing mechanism but no in vitro reconstitution","pmids":["12917321"],"is_preprint":false},{"year":2003,"finding":"TIAR, TIA-1, HuR, and hnRNP U form a multimeric protein-RNA complex that binds specifically to the first 60 nucleotides of the COX-2 mRNA 3'UTR containing multiple AUUUA sequences; insertion of this 60-nt sequence into a heterologous reporter reduces expression by 70%.","method":"EMSA, immunoprecipitation of protein-RNA complex, reporter gene assay, cytoplasmic fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — EMSA and co-IP identifying TIAR in complex, functional reporter, single lab","pmids":["12855701"],"is_preprint":false},{"year":2006,"finding":"Fas-activated serine/threonine kinase (FAST K) synergizes with TIAR (and TIA-1) to promote inclusion of Fas exon 6 (pro-apoptotic isoform); FAST K depletion causes Fas exon 6 skipping; in vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding, connecting Fas signaling to TIAR/TIA-1-regulated splicing.","method":"siRNA depletion of FAST K, minigene reporter transfection, in vitro kinase assay with TIA-1 phosphorylation, U1 snRNP recruitment assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro kinase assay with functional snRNP recruitment readout plus genetic depletion and mutation of TIA-1/TIAR-responsive enhancer, multiple orthogonal methods","pmids":["17135269"],"is_preprint":false},{"year":2005,"finding":"TIAR continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner; RRM2 and the first half of the auxiliary region are important for nuclear accumulation; RRM3 mediates nuclear export via its RNA-binding capacity; RRM2 mutations (RNP2/RNP1) redistribute TIAR to cytoplasm, while RRM3 mutations abolish nuclear export; TIAR nuclear accumulation is Ran-GTP-dependent but export is CRM1-independent.","method":"GFP-fusion domain deletion/point mutant transfection, heterokaryon nuclear export assay, transcription inhibitor treatment, Ran-GTP depletion, LMB (CRM1 inhibitor) treatment, fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain mutants with orthogonal inhibitor treatments and nucleo-cytoplasmic shuttling assays in single study","pmids":["16278295"],"is_preprint":false},{"year":2007,"finding":"TIAR binds a C-rich 28-32 nt stem-loop motif (in addition to U-rich sequences) in the 3'UTRs of target mRNAs in unstressed colon cancer cells; RRM2 and RRM3 domains are sufficient for this binding (verified by surface plasmon resonance); in response to UVC stress, target mRNAs bearing C-rich motifs dissociate from TIAR and encoded protein levels increase in a TIAR-dependent manner.","method":"RNA immunoprecipitation followed by microarray (RIP-chip), surface plasmon resonance (SPR), luciferase reporter, bioinformatic motif analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR quantitative binding plus functional reporter and RIP-chip, single lab","pmids":["17682065"],"is_preprint":false},{"year":2002,"finding":"An alternatively spliced TIAR isoform containing a 17-amino acid insert mediates translational repression of human MMP13 mRNA in human and primate cells; transient expression of this 17-aa insert reverses MMP13 mRNA silencing; co-transfection of the alternatively spliced TIAR with MMP13 in Rat2 cells suppresses MMP13 protein expression, explaining species-specific differences in MMP13 translation.","method":"Transient transfection of TIAR isoforms, Western blot for MMP13 protein, co-transfection reporter assays, species comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, overexpression gain-of-function with multiple cell types and co-transfection validation","pmids":["12426321"],"is_preprint":false},{"year":2007,"finding":"TIAR and TIA-1 are sequestered by West Nile virus (WNV) and dengue virus replication complex components (dsRNA, NS3) in perinuclear regions of infected cells; TIAR relocation correlates with the kinetics of genomic RNA synthesis; virus infection progressively inhibits stress granule induction by arsenite and decreases processing body numbers, suggesting TIAR interaction with viral components facilitates flavivirus genome RNA synthesis and suppresses SG-mediated host translation shutoff.","method":"Immunofluorescence colocalization in infected cells, kinetic analysis, arsenite SG induction assay, processing body quantification, TIAR knockout cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell biology imaging with functional knockout comparison, single lab, no direct binding reconstitution in this paper","pmids":["17502609"],"is_preprint":false},{"year":2005,"finding":"TIAR binds single-stranded thymidine-rich (T-rich) DNA sequences with ~6-fold higher affinity than equivalent RNA sequences (Kd ~1.6 nM for DNA vs ~9.4 nM for RNA); the high-affinity DNA-binding site maps to RRM2, though RRM1 alone can also bind DNA; TIAR cannot bind double-stranded DNA; TIAR can be displaced from ssDNA by active transcription through the binding site.","method":"UV cross-linking, EMSA, filter binding assays with truncation mutants, affinity measurements, in vitro transcription displacement assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay with quantitative Kd measurements, domain deletion mapping, single lab with multiple orthogonal methods","pmids":["16091628"],"is_preprint":false},{"year":2011,"finding":"TIAR and HuR both bind U-rich and AU-rich RNA with nanomolar affinity (higher for U-rich); TIAR binds deoxy-oligonucleotides with nanomolar affinity while HuR affinity for DNA is reduced to micromolar; TIAR binding depends less on 2'-hydroxyl of RNA than HuR; SAXS data indicate that the first two domains of TIAR adopt a flexible elongated shape upon RNA binding rather than the compact shape of Hu proteins, revealing fundamentally different binding modes.","method":"Surface plasmon resonance (SPR), small-angle X-ray scattering (SAXS), comparative binding with DNA/RNA variants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR quantitative binding plus SAXS structural analysis, single lab with multiple orthogonal methods","pmids":["21233170"],"is_preprint":false},{"year":2013,"finding":"RRM2 of TIAR together with its six-residue C-terminal linker extension constitutes the major high-affinity (nM) RNA- and DNA-binding module; RRM1 alone shows preferred DNA over RNA binding; NMR spectroscopy identified specific amino acid residues in RRM2 involved in AU-rich RNA binding; high-affinity U-rich RNA and T-rich DNA binding (nM) requires RRM2 plus the linker, not RRM2 alone.","method":"Surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) spectroscopy, domain truncation analysis","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative SPR and NMR structural characterization with domain truncations identifying specific residues, single lab with multiple orthogonal methods","pmids":["23603827"],"is_preprint":false},{"year":2003,"finding":"DT40 cells require either TIA-1 or TIAR for viability; TIA-1 overexpression in tia-1-/-tiar-/+ cells induces efficient splicing of two TIAR alternative exons containing in-frame stop codons, reducing TIAR levels via nonsense-mediated mRNA decay, revealing a cross-regulatory mechanism where TIA-1 controls TIAR levels through splicing-coupled NMD.","method":"Conditional gene disruption in DT40 cells, RT-PCR for alternative splicing, cycloheximide treatment (NMD assay), TIA-1 expression rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption with functional rescue plus mechanistic splicing/NMD analysis, multiple orthogonal methods","pmids":["12533540"],"is_preprint":false},{"year":2010,"finding":"Under acute/severe hypoxia, TIAR and TIA-1 co-aggregate into stress granules (positive for eIF3η) and simultaneously suppress HIF-1α expression; silencing of TIAR (and TIA-1) upregulates HIF-1α; TIAR acts via a 3'UTR ARE of HIF-1α mRNA to suppress its expression as shown by luciferase reporter assays with the HIF-1α 3'UTR.","method":"Immunostaining, subcellular fractionation, siRNA knockdown, Western blot, luciferase reporter with HIF-1α 3'UTR ARE, immunohistochemistry of tumor xenografts","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with reporter assay and protein level analysis, single lab, multiple methods","pmids":["20980400"],"is_preprint":false},{"year":2018,"finding":"TIAR is essential for the G2/M checkpoint; TIAR accumulates in nuclear foci called G2/M transition granules (GMGs) in late G2 and prophase, particularly under replication stress; GMGs contain CDK1 along with replication stress response and RNA metabolism proteins; TIAR retains CDK1 in GMGs and attenuates CDK1 activity; TIAR depletion accelerates mitotic entry and causes chromosomal instability under replication stress, which is alleviated by Cdc25B depletion or CDK1 inhibition.","method":"siRNA knockdown, immunofluorescence microscopy, cell cycle analysis (flow cytometry), CDK1 activity assay, chromosomal instability assay, epistasis with Cdc25B depletion and CDK1 inhibitor","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown with defined checkpoint phenotype, CDK1 activity assay, and epistasis experiments with multiple orthogonal readouts","pmids":["30538118"],"is_preprint":false},{"year":2009,"finding":"TIAR colocalizes with mutant SOD1 in insoluble aggregates/inclusions in mouse spinal cord and glioma cells; this colocalization is abolished by RNase treatment, indicating it is RNA-mediated; mutant SOD1 expression causes significant loss of VEGF mRNA binding to TIAR, depletion of HuR from polysomes, and reduced VEGF mRNA half-life.","method":"Co-immunoprecipitation with RNase treatment, RNA immunoprecipitation (RIP), immunofluorescence, polysome fractionation, mRNA half-life assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and co-IP with RNase control, single lab, multiple methods but indirect mechanism","pmids":["19805546"],"is_preprint":false},{"year":2014,"finding":"In BCR-ABL1 (CML) leukemia cells, ER stress promotes cytosolic localization of TIAR, its binding to BRCA1 mRNA 3'UTR ARE, and formation of a TIAR-HuR complex; TIAR negatively regulates BRCA1 mRNA translation (shown by polysome profiling and luciferase-BRCA1 3'UTR reporter); silencing of TIAR strongly elevates BRCA1 protein levels.","method":"Polysome profiling, luciferase reporter with BRCA1 3'UTR, RNA immunoprecipitation, siRNA knockdown, subcellular fractionation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling plus reporter plus RIP, single lab, multiple orthogonal methods","pmids":["25483082"],"is_preprint":false},{"year":2023,"finding":"In vivo PAR-CLIP of mouse liver TIAL1 identified Insig2 and ApoB as prominent TIAL1 target transcripts; TIAL1 influences their translation in hepatocytes; Tial1 mutant mice exhibit altered cholesterol synthesis, APOB secretion, and plasma cholesterol levels, placing TIAL1 in the negative feedback regulation of cholesterol biosynthesis.","method":"In vivo PAR-CLIP (viP-CLIP) in mouse liver, translation assay in hepatocytes, Tial1 mutant mice with cholesterol/APOB phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CLIP with functional validation in mouse knockout model showing metabolic phenotype, multiple orthogonal methods","pmids":["37296170"],"is_preprint":false},{"year":2023,"finding":"TIAR binds the 5' stem-loop (ε) of HBV pregenomic RNA (pgRNA) and promotes HBV DNA replication; TIAR increases translation of the polymerase (Pol) while decreasing translation of core protein (Cp) from the same pgRNA template; HBV replication or Cp expression induces TIAR redistribution from nucleus to cytoplasm.","method":"RNA immunoprecipitation, pulldown assay, Ribo-seq, PRM-based mass spectrometry, loss- and gain-of-function genetic analysis","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Ribo-seq and mass spectrometry for translational readout plus RIP/pulldown for binding, loss- and gain-of-function, multiple orthogonal methods","pmids":["37699883"],"is_preprint":false},{"year":2022,"finding":"In pro-B cells, TIA1 and TIAL1 act redundantly as global splicing regulators controlling hundreds of mRNAs; they bind 5' splice sites for exon definition and splicing of DNA damage repair genes (including Chek2 and Rif1); in their absence, pro-B cells show exacerbated DNA damage, altered p53 expression, and increased cell death.","method":"Conditional double knockout in pro-B cells, RNA-seq, iCLIP, RT-PCR splicing validation, DNA damage markers (γH2AX), flow cytometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional double KO with CLIP, RNA-seq, and functional DNA damage readouts, multiple orthogonal methods","pmids":["36543128"],"is_preprint":false},{"year":2023,"finding":"TIA1 and TIAL1 are required for germinal center (GC) B cell survival and differentiation; they control Mcl1 mRNA translation to promote expression of the prosurvival molecule MCL1; TIA1/TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection, expansion, and differentiation into high-affinity antibody-producing clones.","method":"Conditional double knockout mice, GC B cell phenotyping by flow cytometry, polysome profiling for MCL1 translation, Western blot","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional double KO with polysome profiling demonstrating translational mechanism, multiple orthogonal methods","pmids":["37474714"],"is_preprint":false},{"year":2025,"finding":"TIAL1 directly interacts with the core Hippo pathway component SAV1 (protein-protein interaction), disrupting the MST1-SAV1 interaction, thereby suppressing Hippo signaling and activating YAP; this function is independent of TIAL1's RNA-binding activity, as RNA-binding-deficient mutants still interact with SAV1 and suppress Hippo; TIAL1 expression is upregulated by energy surplus and EGF.","method":"Co-immunoprecipitation, domain mutant analysis (RNA-binding deficient mutants), YAP activity reporter, MST1-SAV1 interaction assay, loss/gain-of-function in hepatocellular carcinoma cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with RNA-binding mutants and functional Hippo pathway readout, single lab, recently published with no replication yet","pmids":["42032365"],"is_preprint":false},{"year":2025,"finding":"The first 23 nucleotides of the TIAR 5'UTR are both necessary and sufficient to confer resistance to SARS-CoV-2 Nsp1-mediated translation shutoff; the absence of guanosines within positions 10-18 downstream from the 5' end is a defining sequence feature (not secondary structure) shared between the SARS-CoV-2 leader and the TIAR 5'UTR that confers Nsp1 resistance.","method":"Reporter shutoff assays with 5'UTR truncation and mutation constructs in cells expressing Nsp1","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic reporter mutagenesis identifying necessary and sufficient sequence features, single lab","pmids":["41407513"],"is_preprint":false},{"year":2025,"finding":"Hypoxia-induced lactylation of HMGB1 at K177 drives nuclear export of HMGB1 in a complex with TIAR, promoting stress granule formation in the cytosol; K177R mutation of HMGB1 completely blocks HMGB1-TIAR complex export and subsequent SG formation; other stressors (arsenite, heat shock) trigger TIAR nuclear export and SG assembly independently of HMGB1.","method":"Mass spectrometry of HMGB1 lactylation sites, K-to-R mutant transfection, co-immunoprecipitation of HMGB1-TIAR complex, immunofluorescence for SG formation","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identifying modification site plus functional mutant analysis, single lab, recently published","pmids":["40788094"],"is_preprint":false},{"year":2014,"finding":"TIAR (and TIA-1) bind SIRT1 pre-mRNA and regulate its alternative splicing; TIAL1 knockdown inhibits exon 8 exclusion (decreasing SIRT1-ΔExon8 levels), while HuR promotes exon 8 exclusion, revealing antagonistic regulation of SIRT1 splicing between these two RBPs.","method":"siRNA knockdown of TIA1/TIAL1 and HuR, RT-PCR for SIRT1 splice variants, reporter assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with splice variant quantification, single lab, two RNA-binding proteins compared","pmids":["24566137"],"is_preprint":false},{"year":2009,"finding":"TIA-1 and TIAR binding sites on the WNV 3'(-)SL RNA were mapped to short AU sequences (UAAUU) in two internal loops; mutations that reduce TIAR/TIA-1 binding efficiency progressively decrease intracellular genomic RNA levels and virus production without affecting translation efficiency of mutant RNAs; several mutants rapidly reverted in vivo, indicating TIAR/TIA-1 interaction facilitates asymmetric amplification of genome RNA from the minus-strand template.","method":"Infectious clone mutagenesis, in vitro binding assays, plaque assays, intracellular RNA quantification, reversion analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic site-directed mutagenesis in infectious clone with multiple functional readouts correlating binding affinity with replication efficiency","pmids":["18768985"],"is_preprint":false}],"current_model":"TIAL1/TIAR is a multi-functional RNA-binding protein with three RRMs (RRM2 being the primary high-affinity binding domain for U-rich RNA and T-rich DNA, with the RRM2 C-terminal linker required for nanomolar affinity) that: (1) shuttles between nucleus and cytoplasm (import via RRM2/auxiliary domain in a Ran-GTP-dependent manner; export via RRM3 in a CRM1-independent manner, with hypoxic stress triggering HMGB1-lactylation-dependent cytoplasmic redistribution); (2) promotes assembly of stress granules downstream of eIF-2alpha phosphorylation; (3) represses translation of ARE-containing and C-rich-motif-containing mRNAs (including TNF-alpha, MYC, eIF4A, eIF4E, 5'TOP mRNAs, BRCA1, and MCL1) and facilitates translation of others (Insig2, ApoB, HBV polymerase); (4) activates inclusion of alternative exons with weak 5' splice sites followed by U-rich intronic sequences (covering ~15% of alternative cassette exons genome-wide), including autoregulatory cross-control of TIAR levels through TIA-1-induced NMD-coupled splicing; (5) functions at the G2/M checkpoint by sequestering CDK1 in nuclear G2/M transition granules under replication stress; (6) is essential for primordial germ cell survival, germinal center B cell responses (via MCL1 translation), and pro-B cell DNA repair splicing programs; and (7) can interact with viral RNAs (WNV, dengue, HBV) to facilitate replication, and with proteins (SAV1) in an RNA-binding-independent manner to suppress Hippo signaling."},"narrative":{"mechanistic_narrative":"TIAL1 (TIAR) is a multifunctional RNA-binding protein that couples cellular stress to post-transcriptional control of gene expression, acting as a nucleator of cytoplasmic stress granules, a translational repressor of specific mRNAs, and a sequence-specific regulator of alternative splicing [PMID:10613902, PMID:16537914, PMID:18456862]. Its RNA/DNA recognition is built on three RRMs, of which RRM2 plus a short C-terminal linker constitutes the major high-affinity (nanomolar) module for U-rich RNA and T-rich single-stranded DNA, while RRM1 contributes DNA preference and RRM3 binds a broad RNA population and drives nuclear export [PMID:8576255, PMID:16091628, PMID:23603827]. The two N-terminal domains adopt a flexible elongated conformation upon RNA binding, distinguishing TIAR's binding mode from related Hu proteins [PMID:21233170]. In the cytoplasm, TIAR assembles stress granules downstream of eIF-2alpha phosphorylation and represses translation of ARE- and C-rich-motif-containing target mRNAs including TNF-alpha, MYC, the translation factors eIF4A/eIF4E, 5'TOP mRNAs, HIF-1alpha, and BRCA1, frequently in competition or partnership with HuR and AUF1 [PMID:10613902, PMID:9890998, PMID:21979918, PMID:17486099, PMID:16537914, PMID:17682065, PMID:20980400, PMID:25483082]. In the nucleus, TIAR activates inclusion of alternative cassette exons that carry weak 5' splice sites followed by U-rich intronic stretches—a mechanism covering roughly 15% of alternatively spliced exons genome-wide and including autoregulatory cross-control whereby TIA-1 drives an NMD-coupled TIAR splicing event to set TIAR levels [PMID:11514562, PMID:18456862, PMID:12533540]. TIAR shuttles continuously between nucleus and cytoplasm, with import requiring RRM2/auxiliary regions in a Ran-GTP-dependent manner and CRM1-independent export via RRM3, and it redistributes to the cytoplasm under apoptotic and stress signals [PMID:7533298, PMID:16278295]. Through these activities TIAR is essential for primordial germ cell survival, governs a G2/M checkpoint by sequestering and attenuating CDK1 in nuclear G2/M transition granules under replication stress, and supports germinal-center B-cell survival via MCL1 translation and pro-B-cell DNA-repair splicing programs [PMID:9482885, PMID:30538118, PMID:36543128, PMID:37474714]. TIAR is additionally co-opted by viral RNAs to facilitate flavivirus (West Nile, dengue) genome amplification and HBV replication, and it suppresses Hippo signaling through an RNA-binding-independent protein interaction with SAV1 [PMID:12414941, PMID:17502609, PMID:37699883, PMID:42032365, PMID:18768985].","teleology":[{"year":1996,"claim":"Established which domain confers TIAR's RNA-binding specificity, defining RRM2 as the determinant of U-rich sequence recognition.","evidence":"SELEX from random RNA pools with domain deletion mutants and filter-binding affinity measurement","pmids":["8576255"],"confidence":"High","gaps":["Did not resolve atomic contacts or the role of the C-terminal linker","RRM1's apparent inability to bind RNA later contrasted with its DNA binding"]},{"year":1995,"claim":"Showed that TIAR localization is stimulus-responsive, redistributing from nucleus to cytoplasm during apoptosis before DNA fragmentation.","evidence":"Immunofluorescence and fractionation during Fas-mediated apoptosis time course","pmids":["7533298"],"confidence":"High","gaps":["Did not define the signal or transport machinery driving redistribution","Functional consequence of cytoplasmic TIAR not mechanistically dissected here"]},{"year":1998,"claim":"Demonstrated an essential physiological requirement for TIAR in primordial germ cell survival via knockout phenotype.","evidence":"TIAR knockout mouse with embryo histology and ES cell proliferation assay","pmids":["9482885"],"confidence":"High","gaps":["Did not identify the mRNA targets responsible for PGC survival","Molecular basis of the ES cell LIF-dependent proliferation defect unresolved"]},{"year":1999,"claim":"Placed TIAR/TIA-1 downstream of eIF-2alpha phosphorylation as a nucleator of stress granule assembly and translational arrest.","evidence":"Phosphomimetic/nonphosphorylatable eIF-2alpha mutants and dominant-negative TIA-1, fluorescence microscopy","pmids":["10613902"],"confidence":"High","gaps":["Did not define which RNAs are recruited into granules","Mechanism of self-aggregation/granule nucleation not resolved"]},{"year":1999,"claim":"Connected TIAR to a defined cytokine mRNA target by showing ARE-dependent binding to TNF-alpha mRNA.","evidence":"EMSA and immunoprecipitation in macrophage cytoplasmic fractions","pmids":["9890998"],"confidence":"Medium","gaps":["Functional translational repression inferred, not directly demonstrated in this study","Single lab without reciprocal validation"]},{"year":2001,"claim":"Defined TIAR's splicing-activator mechanism: recognition of U-rich intronic stretches downstream of weak 5' splice sites, including autoregulatory exons.","evidence":"In vitro splicing assays and minigene reporters with U-rich deletion mutagenesis","pmids":["11514562"],"confidence":"High","gaps":["Did not establish genome-wide scope at this stage","snRNP recruitment mechanism not yet defined"]},{"year":2002,"claim":"Revealed that TIAR is hijacked by a viral RNA element, binding the WNV minus-strand 3' stem-loop and supporting replication.","evidence":"RNA affinity purification, Kd measurement, and virus growth in knockout/reconstituted cells","pmids":["12414941"],"confidence":"High","gaps":["Mechanism by which binding promotes replication not yet defined here","Distinction between TIAR and TIA-1 roles unresolved"]},{"year":2003,"claim":"Established a self-regulatory circuit whereby TIA-1 controls TIAR abundance through splicing-coupled NMD.","evidence":"Conditional gene disruption in DT40 cells with RT-PCR, cycloheximide NMD assay, and rescue","pmids":["12533540"],"confidence":"High","gaps":["Did not map the full set of co-regulated targets","Physiological setting of autoregulation in mammalian tissues unaddressed here"]},{"year":2003,"claim":"Showed mechanistic interplay between TIAR and the spliceosome, with synergistic U6 snRNA recruitment at a pseudo 5' splice site enhancer.","evidence":"UV cross-linking, EMSA, dominant-negative TIAR, and minigene reporters with snRNA interaction analysis","pmids":["12917321"],"confidence":"Medium","gaps":["No in vitro reconstitution of the synergistic complex","Single-lab evidence"]},{"year":2006,"claim":"Identified translation factor mRNAs and c-Myc as direct TIAR-repressed targets mediating UVC-induced translational shutdown.","evidence":"RIP, reporters, siRNA rescue, and polysome profiling under UVC stress","pmids":["16537914"],"confidence":"High","gaps":["Did not establish whether repression occurs in stress granules or by direct initiation block","Selectivity rules among 3'UTR targets unresolved"]},{"year":2007,"claim":"Demonstrated competitive control of MYC mRNA between TIAR and AUF1, linking TIAR abundance inversely to proliferation.","evidence":"RIP, reporters, siRNA/overexpression, and proliferation assays with genetic epistasis","pmids":["17486099"],"confidence":"High","gaps":["Molecular basis of the reciprocal binding competition not structurally defined","Generality across other ARE targets not tested"]},{"year":2007,"claim":"Expanded TIAR's binding repertoire beyond U-rich motifs to a C-rich stem-loop and showed stress-induced dissociation derepresses targets.","evidence":"RIP-chip, SPR binding, and luciferase reporters under UVC stress","pmids":["17682065"],"confidence":"Medium","gaps":["Signal triggering target release from TIAR under stress not identified","Single-lab characterization of C-rich binding mode"]},{"year":2008,"claim":"Quantified the genome-wide scope of TIA1/TIAL1-dependent splicing, attributing ~15% of cassette exon regulation to U-rich intronic motifs.","evidence":"Double siRNA knockdown with splicing microarray, RT-PCR validation, and motif analysis","pmids":["18456862"],"confidence":"High","gaps":["Redundancy partitioning between TIA1 and TIAL1 not resolved per-target","Tissue-specific splicing programs not addressed"]},{"year":2011,"claim":"Defined the 5'TOP mRNA arrest mechanism, showing TIAR assembles on 5' ends to block initiation under amino acid starvation via GCN2/mTOR signaling.","evidence":"RIP, polysome profiling, siRNA, reporters, and stress granule imaging","pmids":["21979918"],"confidence":"High","gaps":["Direct contact between TIAR and 5'TOP elements not structurally mapped","Relationship to canonical TOP regulators left open"]},{"year":2011,"claim":"Provided structural insight distinguishing TIAR from Hu proteins, with a flexible elongated conformation and unusually strong DNA binding.","evidence":"SPR and SAXS with DNA/RNA variant comparison","pmids":["21233170"],"confidence":"High","gaps":["No high-resolution complex structure","Functional importance of the elongated conformation in cells untested"]},{"year":2013,"claim":"Pinpointed the minimal high-affinity module as RRM2 plus a six-residue C-terminal linker, identifying residues engaging AU-rich RNA.","evidence":"SPR and NMR with domain truncations","pmids":["23603827"],"confidence":"High","gaps":["Linker's structural role not fully visualized in a complex","How RRM1 and RRM3 cooperate with RRM2 in vivo unresolved"]},{"year":2018,"claim":"Uncovered a nuclear G2/M checkpoint function in which TIAR sequesters and attenuates CDK1 in transition granules under replication stress.","evidence":"siRNA, immunofluorescence, flow cytometry, CDK1 activity assay, and epistasis with Cdc25B/CDK1 inhibition","pmids":["30538118"],"confidence":"High","gaps":["Whether RNA binding is required for GMG assembly not resolved","Composition and biogenesis of GMGs only partially defined"]},{"year":2022,"claim":"Established a developmental splicing program in which TIA1/TIAL1 redundantly control DNA-repair gene splicing to protect pro-B cells.","evidence":"Conditional double knockout with iCLIP, RNA-seq, splicing RT-PCR, and DNA damage readouts","pmids":["36543128"],"confidence":"High","gaps":["Individual contributions of Chek2 vs Rif1 mis-splicing to the phenotype not isolated","Whether translational targets also contribute unaddressed"]},{"year":2023,"claim":"Demonstrated an in vivo metabolic role, with hepatic TIAL1 controlling Insig2/ApoB translation and cholesterol homeostasis.","evidence":"In vivo PAR-CLIP in mouse liver, hepatocyte translation assays, and Tial1 mutant cholesterol/APOB phenotyping","pmids":["37296170"],"confidence":"High","gaps":["Whether translation is enhanced or repressed per target not uniformly resolved","Mechanistic link to the cholesterol feedback loop only correlative"]},{"year":2023,"claim":"Showed TIAR differentially controls translation of two proteins from one HBV pgRNA template via 5' stem-loop binding to promote replication.","evidence":"RIP/pulldown, Ribo-seq, PRM mass spectrometry, and loss/gain-of-function","pmids":["37699883"],"confidence":"High","gaps":["Mechanism producing opposite effects on Pol vs Cp not resolved","Trigger for TIAR nuclear-to-cytoplasm redistribution during infection unclear"]},{"year":2023,"claim":"Identified MCL1 mRNA translation as the TIA1/TIAL1-dependent pathway sustaining germinal center B-cell survival and selection.","evidence":"Conditional double knockout mice with GC phenotyping and polysome profiling","pmids":["37474714"],"confidence":"High","gaps":["Whether MCL1 is a direct binding target shown by CLIP not established here","Contribution of splicing vs translational control to the phenotype not separated"]},{"year":2025,"claim":"Revealed an RNA-binding-independent function: TIAL1 binds SAV1 to disrupt MST1-SAV1 and suppress Hippo signaling, activating YAP.","evidence":"Co-IP, RNA-binding-deficient mutants, YAP reporter, and MST1-SAV1 interaction assays in HCC cells","pmids":["42032365"],"confidence":"Medium","gaps":["Recently published without independent replication","Structural basis of the TIAL1-SAV1 interaction undefined"]},{"year":2025,"claim":"Linked hypoxia metabolism to TIAR trafficking via HMGB1 K177 lactylation driving HMGB1-TIAR co-export and stress granule formation.","evidence":"Mass spectrometry of lactylation sites, K177R mutant, co-IP, and SG imaging","pmids":["40788094"],"confidence":"Medium","gaps":["Single-lab and recently published","How the HMGB1-TIAR complex nucleates SGs mechanistically unresolved"]},{"year":2025,"claim":"Defined a sequence determinant in the TIAR 5'UTR that confers resistance to SARS-CoV-2 Nsp1 translation shutoff.","evidence":"Reporter shutoff assays with 5'UTR truncation/mutation constructs","pmids":["41407513"],"confidence":"Medium","gaps":["Does not establish the cellular consequence of TIAR escaping shutoff","Mechanism by which guanosine absence confers resistance not biochemically resolved"]},{"year":null,"claim":"How TIAR's distinct activities—splicing activation, translational repression, granule nucleation, and RNA-binding-independent signaling—are coordinated and switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking domain conformation to functional mode switching","Signal-specific rules governing TIAR localization and target selection undefined","No high-resolution structure of TIAR bound to a physiological target"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,15,19,20,26,28]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[18,19,20]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[3,6,7,22,25,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,10,11,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,14,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,8,17]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,14,23]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,10,21,28]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,3,22,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,7,25,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,17,27,34]}],"complexes":["stress granule","G2/M transition granules (GMGs)"],"partners":["TIA1","HUR","AUF1","HNRNP U","CDK1","SAV1","HMGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01085","full_name":"Nucleolysin TIAR","aliases":["TIA-1-related protein"],"length_aa":375,"mass_kda":41.6,"function":"RNA-binding protein involved in alternative pre-RNA splicing and in cytoplasmic stress granules formation (PubMed:10613902, PubMed:1326761, PubMed:17488725, PubMed:8576255). Shows a preference for uridine-rich RNAs (PubMed:8576255). Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIA1 mRNA (By similarity). Promotes the inclusion of TIA1 exon 5 to give rise to the long isoform (isoform a) of TIA1 (PubMed:17488725). Acts downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SG) (PubMed:10613902). Possesses nucleolytic activity against cytotoxic lymphocyte target cells (PubMed:1326761). May be involved in apoptosis (PubMed:1326761)","subcellular_location":"Nucleus; Cytoplasm; Cytolytic granule; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q01085/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TIAL1","classification":"Not Classified","n_dependent_lines":119,"n_total_lines":1208,"dependency_fraction":0.09850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EMC9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TIAL1","total_profiled":1310},"omim":[{"mim_id":"614392","title":"TUDOR DOMAIN-CONTAINING PROTEIN 3; TDRD3","url":"https://www.omim.org/entry/614392"},{"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":"603413","title":"TIA1 CYTOTOXIC GRANULE-ASSOCIATED RNA-BINDING PROTEIN-LIKE 1; TIAL1","url":"https://www.omim.org/entry/603413"},{"mim_id":"601937","title":"NUCLEAR RECEPTOR COACTIVATOR 3; NCOA3","url":"https://www.omim.org/entry/601937"}],"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/TIAL1"},"hgnc":{"alias_symbol":["TIAR"],"prev_symbol":[]},"alphafold":{"accession":"Q01085","domains":[{"cath_id":"3.30.70.330","chopping":"9-81","consensus_level":"high","plddt":89.8311,"start":9,"end":81},{"cath_id":"3.30.70.330","chopping":"96-171","consensus_level":"high","plddt":92.1014,"start":96,"end":171},{"cath_id":"3.30.70.330","chopping":"192-273","consensus_level":"high","plddt":93.3304,"start":192,"end":273}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01085","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01085-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01085-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TIAL1","jax_strain_url":"https://www.jax.org/strain/search?query=TIAL1"},"sequence":{"accession":"Q01085","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01085.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01085/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01085"}},"corpus_meta":[{"pmid":"10613902","id":"PMC_10613902","title":"RNA-binding 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America","url":"https://pubmed.ncbi.nlm.nih.gov/9482885","citation_count":162,"is_preprint":false},{"pmid":"12414941","id":"PMC_12414941","title":"Cell proteins TIA-1 and TIAR interact with the 3' stem-loop of the West Nile virus complementary minus-strand RNA and facilitate virus replication.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12414941","citation_count":156,"is_preprint":false},{"pmid":"17486099","id":"PMC_17486099","title":"Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation.","date":"2007","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17486099","citation_count":156,"is_preprint":false},{"pmid":"16537914","id":"PMC_16537914","title":"Translational repression by RNA-binding protein TIAR.","date":"2006","source":"Molecular and cellular 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U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation.","date":"2008","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/18456862","citation_count":87,"is_preprint":false},{"pmid":"8871565","id":"PMC_8871565","title":"Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8871565","citation_count":86,"is_preprint":false},{"pmid":"17135269","id":"PMC_17135269","title":"Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17135269","citation_count":72,"is_preprint":false},{"pmid":"15280467","id":"PMC_15280467","title":"Herpes simplex virus 1 induces cytoplasmic accumulation of TIA-1/TIAR and both synthesis and cytoplasmic accumulation of 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France)","url":"https://pubmed.ncbi.nlm.nih.gov/16191398","citation_count":12,"is_preprint":false},{"pmid":"27699280","id":"PMC_27699280","title":"PTB and TIAR binding to insulin mRNA 3'- and 5'UTRs; implications for insulin biosynthesis and messenger stability.","date":"2016","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/27699280","citation_count":12,"is_preprint":false},{"pmid":"30569136","id":"PMC_30569136","title":"miR‑223‑3p/TIAL1 interaction is involved in the mechanisms associated with the neuroprotective effects of dexmedetomidine on hippocampal neuronal cells in vitro.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/30569136","citation_count":12,"is_preprint":false},{"pmid":"24927121","id":"PMC_24927121","title":"Genome-wide profiling reveals a role for T-cell intracellular antigens TIA1 and TIAR in the control of translational specificity in HeLa cells.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24927121","citation_count":12,"is_preprint":false},{"pmid":"26363455","id":"PMC_26363455","title":"TIA-1 and TIAR interact with 5'-UTR of enterovirus 71 genome and facilitate viral replication.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26363455","citation_count":10,"is_preprint":false},{"pmid":"37296170","id":"PMC_37296170","title":"In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37296170","citation_count":10,"is_preprint":false},{"pmid":"9631446","id":"PMC_9631446","title":"Increased expression of the TIAR protein in the hippocampus of Alzheimer patients.","date":"1998","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/9631446","citation_count":9,"is_preprint":false},{"pmid":"19339348","id":"PMC_19339348","title":"Splicing of the large intron present in the nonstructural gene of minute virus of mice is governed by TIA-1/TIAR binding downstream of the nonconsensus donor.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19339348","citation_count":8,"is_preprint":false},{"pmid":"37123244","id":"PMC_37123244","title":"TIAR and FMRP shape pro-survival nascent proteome of leukemia cells in the bone marrow microenvironment.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37123244","citation_count":7,"is_preprint":false},{"pmid":"25918534","id":"PMC_25918534","title":"Targeted Knockdown of RNA-Binding Protein TIAR for Promoting Self-Renewal and Attenuating Differentiation of Mouse Embryonic Stem Cells.","date":"2015","source":"Stem cells international","url":"https://pubmed.ncbi.nlm.nih.gov/25918534","citation_count":7,"is_preprint":false},{"pmid":"26981431","id":"PMC_26981431","title":"Genome-wide analysis of TIAR RNA ligands in mouse macrophages before and after LPS stimulation.","date":"2016","source":"Genomics data","url":"https://pubmed.ncbi.nlm.nih.gov/26981431","citation_count":7,"is_preprint":false},{"pmid":"20675271","id":"PMC_20675271","title":"Identification of chosen apoptotic (TIAR and TIA-1) markers expression in thyroid tissues from adolescents with immune and non-immune thyroid diseases.","date":"2010","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/20675271","citation_count":7,"is_preprint":false},{"pmid":"40788094","id":"PMC_40788094","title":"Lactylation of HMGB1 at K177 Drives Nuclear Export of TIAR to Promote Hypoxia-Induced Stress Granule Formation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40788094","citation_count":6,"is_preprint":false},{"pmid":"35367339","id":"PMC_35367339","title":"The TIAR-mediated Nrf2 response to oxidative stress is mediated through the Nrf2 noncoding 3'untranslated region in Spodoptera litura.","date":"2022","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35367339","citation_count":6,"is_preprint":false},{"pmid":"33896245","id":"PMC_33896245","title":"MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33896245","citation_count":5,"is_preprint":false},{"pmid":"37604264","id":"PMC_37604264","title":"The stress granule component TIAR during the non-embryonic development of the colonial ascidian Botryllusschlosseri.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37604264","citation_count":5,"is_preprint":false},{"pmid":"37667420","id":"PMC_37667420","title":"Depletion of TIAR impairs embryogenesis via inhibiting zygote genome transcribe.","date":"2023","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/37667420","citation_count":3,"is_preprint":false},{"pmid":"38161334","id":"PMC_38161334","title":"Two predicted α-helices within the prion-like domain of TIAR-1 play a crucial role in its association with stress granules in Caenorhabditis elegans.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38161334","citation_count":3,"is_preprint":false},{"pmid":"41407513","id":"PMC_41407513","title":"Escape from SARS-CoV-2 Nsp1-mediated host shutoff by TIAR transcript reveals general features of Nsp1 resistance.","date":"2026","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41407513","citation_count":1,"is_preprint":false},{"pmid":"42032365","id":"PMC_42032365","title":"TIAL1 regulates the Hippo pathway through an RNA-binding-independent mechanism.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/42032365","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.20.648873","title":"TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.20.648873","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.28.685039","title":"Distinct Cellular Effects of Myotonic Dystrophy type 2 RAN Tetrapeptides in  <i>Drosophila melanogaster</i>","date":"2025-10-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685039","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.03.608755","title":"Post-transcriptional regulation by TIA1 and TIAL1 controls the transcriptional program enforcing T cell quiescence","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.03.608755","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.20.665556","title":"Molecular and structural remodeling of stress granules in slowly and rapidly progressive Alzheimer’s disease","date":"2025-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.20.665556","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33860,"output_tokens":9400,"usd":0.12129,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19758,"output_tokens":6594,"usd":0.13182,"stage2_stop_reason":"end_turn"},"total_usd":0.25311,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TIAR (and TIA-1) colocalize with poly(A)+ RNA at cytoplasmic stress granules; stress granule assembly is initiated downstream of eIF-2alpha phosphorylation at S51, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of stress granule formation, placing TIAR/TIA-1 downstream of eIF-2alpha phosphorylation in the stress-induced translational arrest pathway.\",\n      \"method\": \"Fluorescence microscopy, phosphomimetic (S51D) and nonphosphorylatable (S51A) eIF-2alpha mutant transfection, dominant-negative TIA-1 mutant transfection\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with phosphomimetic mutants plus dominant-negative approach, replicated across multiple stress conditions in single rigorous study\",\n      \"pmids\": [\"10613902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TIAR binds to the AU-rich element (ARE) of TNF-alpha mRNA (complex 1 requiring clustered AUUUA pentamers) in the cytoplasm of macrophages, implicating TIAR in post-transcriptional regulation of TNF-alpha translation.\",\n      \"method\": \"RNA electrophoretic mobility shift assay (EMSA), protein identification by immunoprecipitation, cytoplasmic localization by fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, EMSA and immunoprecipitation, two orthogonal methods identifying TIAR in complex\",\n      \"pmids\": [\"9890998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RRM2 of both TIA-1 and TIAR is the primary domain mediating specific binding to uridylate-rich RNA sequences; RRM1 does not bind RNA due to negatively charged residues in the RNP1 octamer; RRM3 binds a broad population of cellular RNAs but not uridylate-rich sequences selected by full-length protein. Affinity for selected RNA increases when RRM2 is expressed with RRM1 and RRM3 (Kd ~20 nM) vs. RRM2 alone (Kd ~50 nM).\",\n      \"method\": \"In vitro selection/amplification (SELEX) from random RNA pools, filter binding assays, domain deletion/mutant expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with domain mutagenesis and quantitative binding assays in single rigorous study\",\n      \"pmids\": [\"8576255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Upon amino acid starvation, TIA-1 and TIAR assemble onto the 5' ends of 5'TOP mRNAs and arrest translation at the initiation step, causing polysome release and accumulation of 5'TOP mRNAs in stress granules; this requires GCN2 kinase activation and mTOR pathway inactivation.\",\n      \"method\": \"RNA immunoprecipitation, polysome profiling, siRNA knockdown, luciferase reporter assays, stress granule imaging\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, polysome profiling, genetic knockdown, reporters) in single study demonstrating translational repression mechanism\",\n      \"pmids\": [\"21979918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TIAR is essential for primordial germ cell (PGC) survival; TIAR-deficient mice fail to develop spermatogonia or oogonia due to reduced PGC survival after migration to the genital ridge by E11.5, with complete PGC absence by E13.5. TIAR-deficient embryonic stem cells also fail to proliferate without exogenous LIF in methylcellulose culture.\",\n      \"method\": \"TIAR knockout mouse generation, embryo histology, timed developmental analysis, in vitro methylcellulose colony assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined developmental phenotype and two orthogonal readouts (in vivo PGC counting, in vitro ES cell proliferation)\",\n      \"pmids\": [\"9482885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIAR (p42) specifically binds the 3' terminal stem-loop of West Nile virus minus-strand RNA (WNV 3'(-)SL RNA) via RRM2 with Kd ~15 nM; TIA-1 also binds but with ~7-fold lower affinity (Kd ~112 nM). WNV replication is less efficient in TIAR knockout cells, and reconstitution with TIAR partially restores WNV growth, indicating a functional role for TIAR in WNV replication.\",\n      \"method\": \"RNA affinity column purification, peptide sequencing, UV cross-linking/immunoprecipitation, competition gel mobility shift assay, recombinant protein binding, TIAR knockout cell lines with virus growth assay and reconstitution\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical binding mapped to specific domain with Kd measurement plus functional reconstitution in knockout cells\",\n      \"pmids\": [\"12414941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AUF1 and TIAR compete for binding to the ARE of MYC mRNA; TIAR acts as a translational suppressor of MYC, and cell proliferation levels are inversely proportional to TIAR abundance. Altering association of one ARE-binding protein with MYC mRNA reciprocally affects the other's association; genetic experiments show AUF1 and TIAR control proliferation through a MYC-dependent pathway.\",\n      \"method\": \"RNA immunoprecipitation, reporter assays, siRNA knockdown/overexpression, cell proliferation assays, mRNA abundance measurements\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, reporters, genetic epistasis) in single rigorous study demonstrating competitive translational repression mechanism\",\n      \"pmids\": [\"17486099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TIAR selectively binds the 3'UTRs of mRNAs encoding translation factors (eIF4A, eIF4E, eEF1B) and c-Myc and potently suppresses their translation, particularly in response to UVC irradiation; siRNA silencing of TIAR significantly relieves UVC-induced global translational inhibition.\",\n      \"method\": \"RNA immunoprecipitation, reporter assays, siRNA knockdown, polysome profiling, UV irradiation stress assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP, functional reporters, and siRNA rescue with multiple target mRNAs validated in single study\",\n      \"pmids\": [\"16537914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TIAR is concentrated in the nucleus of hematopoietic and nonhematopoietic cells under normal conditions, but translocates from nucleus to cytoplasm within 30 min of Fas ligation during apoptosis, preceding the onset of DNA fragmentation; this redistribution is specific to apoptosis and not observed during mitogen-induced activation.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, Western blot, Fas-mediated apoptosis induction, time-course analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence (precedes DNA fragmentation), two orthogonal methods, specific to apoptotic stimulus\",\n      \"pmids\": [\"7533298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIAR activates splicing of alternative exons with weak 5' splice sites followed by U-rich stretches, including autoregulatory exons on the TIAR and TIA-1 pre-mRNAs; TIA-1 directly activates TIAR alternative exon 5' splice sites in vitro requiring a downstream U-rich stretch of at least 10 residues. TIAR overexpression induces use of cryptic 5' splice sites that are also followed by U-rich sequences when the native U-rich stretch is deleted.\",\n      \"method\": \"Overexpression in cells, in vitro splicing assays, minigene reporters, deletion mutagenesis of U-rich sequences\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro splicing reconstitution with mutagenesis establishing U-rich sequence requirement, supported by cell-based overexpression data\",\n      \"pmids\": [\"11514562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TIA1 and TIAL1 regulate inclusion of ~15% of alternative cassette exons genome-wide via U-rich intronic motifs downstream of 5' splice sites; simultaneous knockdown of TIA1 and TIAL1 caused skipping of 88% of alternatively spliced exons associated with U-rich motifs but did not affect 97% of exons lacking such motifs; exon skipping correlated with proximity and U-richness of adjacent intronic region.\",\n      \"method\": \"Simultaneous siRNA knockdown of TIA1 and TIAL1, splicing-sensitive microarray, RT-PCR validation, bioinformatic motif analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale functional screen with validated double knockdown and multiple RT-PCR confirmations across many targets\",\n      \"pmids\": [\"18456862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIAR binds to a U-tract sequence motif downstream of a pseudo 5' splice site within the calcitonin/CGRP intron enhancer and promotes inclusion of the alternative 3'-terminal exon >200 nt upstream; TIAR's binding depends on U1 and U6 snRNA interactions with the pseudo 5' splice site, and TIAR binding in turn promotes U6 snRNA binding (synergistic relationship).\",\n      \"method\": \"UV cross-linking, EMSA, dominant-negative TIAR mutant overexpression, minigene reporter assays, snRNA interaction analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple methods (UV cross-linking, dominant-negative, reporters) establishing mechanism but no in vitro reconstitution\",\n      \"pmids\": [\"12917321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIAR, TIA-1, HuR, and hnRNP U form a multimeric protein-RNA complex that binds specifically to the first 60 nucleotides of the COX-2 mRNA 3'UTR containing multiple AUUUA sequences; insertion of this 60-nt sequence into a heterologous reporter reduces expression by 70%.\",\n      \"method\": \"EMSA, immunoprecipitation of protein-RNA complex, reporter gene assay, cytoplasmic fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — EMSA and co-IP identifying TIAR in complex, functional reporter, single lab\",\n      \"pmids\": [\"12855701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fas-activated serine/threonine kinase (FAST K) synergizes with TIAR (and TIA-1) to promote inclusion of Fas exon 6 (pro-apoptotic isoform); FAST K depletion causes Fas exon 6 skipping; in vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding, connecting Fas signaling to TIAR/TIA-1-regulated splicing.\",\n      \"method\": \"siRNA depletion of FAST K, minigene reporter transfection, in vitro kinase assay with TIA-1 phosphorylation, U1 snRNP recruitment assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro kinase assay with functional snRNP recruitment readout plus genetic depletion and mutation of TIA-1/TIAR-responsive enhancer, multiple orthogonal methods\",\n      \"pmids\": [\"17135269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIAR continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner; RRM2 and the first half of the auxiliary region are important for nuclear accumulation; RRM3 mediates nuclear export via its RNA-binding capacity; RRM2 mutations (RNP2/RNP1) redistribute TIAR to cytoplasm, while RRM3 mutations abolish nuclear export; TIAR nuclear accumulation is Ran-GTP-dependent but export is CRM1-independent.\",\n      \"method\": \"GFP-fusion domain deletion/point mutant transfection, heterokaryon nuclear export assay, transcription inhibitor treatment, Ran-GTP depletion, LMB (CRM1 inhibitor) treatment, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain mutants with orthogonal inhibitor treatments and nucleo-cytoplasmic shuttling assays in single study\",\n      \"pmids\": [\"16278295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIAR binds a C-rich 28-32 nt stem-loop motif (in addition to U-rich sequences) in the 3'UTRs of target mRNAs in unstressed colon cancer cells; RRM2 and RRM3 domains are sufficient for this binding (verified by surface plasmon resonance); in response to UVC stress, target mRNAs bearing C-rich motifs dissociate from TIAR and encoded protein levels increase in a TIAR-dependent manner.\",\n      \"method\": \"RNA immunoprecipitation followed by microarray (RIP-chip), surface plasmon resonance (SPR), luciferase reporter, bioinformatic motif analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR quantitative binding plus functional reporter and RIP-chip, single lab\",\n      \"pmids\": [\"17682065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"An alternatively spliced TIAR isoform containing a 17-amino acid insert mediates translational repression of human MMP13 mRNA in human and primate cells; transient expression of this 17-aa insert reverses MMP13 mRNA silencing; co-transfection of the alternatively spliced TIAR with MMP13 in Rat2 cells suppresses MMP13 protein expression, explaining species-specific differences in MMP13 translation.\",\n      \"method\": \"Transient transfection of TIAR isoforms, Western blot for MMP13 protein, co-transfection reporter assays, species comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, overexpression gain-of-function with multiple cell types and co-transfection validation\",\n      \"pmids\": [\"12426321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIAR and TIA-1 are sequestered by West Nile virus (WNV) and dengue virus replication complex components (dsRNA, NS3) in perinuclear regions of infected cells; TIAR relocation correlates with the kinetics of genomic RNA synthesis; virus infection progressively inhibits stress granule induction by arsenite and decreases processing body numbers, suggesting TIAR interaction with viral components facilitates flavivirus genome RNA synthesis and suppresses SG-mediated host translation shutoff.\",\n      \"method\": \"Immunofluorescence colocalization in infected cells, kinetic analysis, arsenite SG induction assay, processing body quantification, TIAR knockout cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell biology imaging with functional knockout comparison, single lab, no direct binding reconstitution in this paper\",\n      \"pmids\": [\"17502609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIAR binds single-stranded thymidine-rich (T-rich) DNA sequences with ~6-fold higher affinity than equivalent RNA sequences (Kd ~1.6 nM for DNA vs ~9.4 nM for RNA); the high-affinity DNA-binding site maps to RRM2, though RRM1 alone can also bind DNA; TIAR cannot bind double-stranded DNA; TIAR can be displaced from ssDNA by active transcription through the binding site.\",\n      \"method\": \"UV cross-linking, EMSA, filter binding assays with truncation mutants, affinity measurements, in vitro transcription displacement assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with quantitative Kd measurements, domain deletion mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16091628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIAR and HuR both bind U-rich and AU-rich RNA with nanomolar affinity (higher for U-rich); TIAR binds deoxy-oligonucleotides with nanomolar affinity while HuR affinity for DNA is reduced to micromolar; TIAR binding depends less on 2'-hydroxyl of RNA than HuR; SAXS data indicate that the first two domains of TIAR adopt a flexible elongated shape upon RNA binding rather than the compact shape of Hu proteins, revealing fundamentally different binding modes.\",\n      \"method\": \"Surface plasmon resonance (SPR), small-angle X-ray scattering (SAXS), comparative binding with DNA/RNA variants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR quantitative binding plus SAXS structural analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21233170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RRM2 of TIAR together with its six-residue C-terminal linker extension constitutes the major high-affinity (nM) RNA- and DNA-binding module; RRM1 alone shows preferred DNA over RNA binding; NMR spectroscopy identified specific amino acid residues in RRM2 involved in AU-rich RNA binding; high-affinity U-rich RNA and T-rich DNA binding (nM) requires RRM2 plus the linker, not RRM2 alone.\",\n      \"method\": \"Surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) spectroscopy, domain truncation analysis\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative SPR and NMR structural characterization with domain truncations identifying specific residues, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23603827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DT40 cells require either TIA-1 or TIAR for viability; TIA-1 overexpression in tia-1-/-tiar-/+ cells induces efficient splicing of two TIAR alternative exons containing in-frame stop codons, reducing TIAR levels via nonsense-mediated mRNA decay, revealing a cross-regulatory mechanism where TIA-1 controls TIAR levels through splicing-coupled NMD.\",\n      \"method\": \"Conditional gene disruption in DT40 cells, RT-PCR for alternative splicing, cycloheximide treatment (NMD assay), TIA-1 expression rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption with functional rescue plus mechanistic splicing/NMD analysis, multiple orthogonal methods\",\n      \"pmids\": [\"12533540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Under acute/severe hypoxia, TIAR and TIA-1 co-aggregate into stress granules (positive for eIF3η) and simultaneously suppress HIF-1α expression; silencing of TIAR (and TIA-1) upregulates HIF-1α; TIAR acts via a 3'UTR ARE of HIF-1α mRNA to suppress its expression as shown by luciferase reporter assays with the HIF-1α 3'UTR.\",\n      \"method\": \"Immunostaining, subcellular fractionation, siRNA knockdown, Western blot, luciferase reporter with HIF-1α 3'UTR ARE, immunohistochemistry of tumor xenografts\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with reporter assay and protein level analysis, single lab, multiple methods\",\n      \"pmids\": [\"20980400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIAR is essential for the G2/M checkpoint; TIAR accumulates in nuclear foci called G2/M transition granules (GMGs) in late G2 and prophase, particularly under replication stress; GMGs contain CDK1 along with replication stress response and RNA metabolism proteins; TIAR retains CDK1 in GMGs and attenuates CDK1 activity; TIAR depletion accelerates mitotic entry and causes chromosomal instability under replication stress, which is alleviated by Cdc25B depletion or CDK1 inhibition.\",\n      \"method\": \"siRNA knockdown, immunofluorescence microscopy, cell cycle analysis (flow cytometry), CDK1 activity assay, chromosomal instability assay, epistasis with Cdc25B depletion and CDK1 inhibitor\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown with defined checkpoint phenotype, CDK1 activity assay, and epistasis experiments with multiple orthogonal readouts\",\n      \"pmids\": [\"30538118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TIAR colocalizes with mutant SOD1 in insoluble aggregates/inclusions in mouse spinal cord and glioma cells; this colocalization is abolished by RNase treatment, indicating it is RNA-mediated; mutant SOD1 expression causes significant loss of VEGF mRNA binding to TIAR, depletion of HuR from polysomes, and reduced VEGF mRNA half-life.\",\n      \"method\": \"Co-immunoprecipitation with RNase treatment, RNA immunoprecipitation (RIP), immunofluorescence, polysome fractionation, mRNA half-life assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and co-IP with RNase control, single lab, multiple methods but indirect mechanism\",\n      \"pmids\": [\"19805546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In BCR-ABL1 (CML) leukemia cells, ER stress promotes cytosolic localization of TIAR, its binding to BRCA1 mRNA 3'UTR ARE, and formation of a TIAR-HuR complex; TIAR negatively regulates BRCA1 mRNA translation (shown by polysome profiling and luciferase-BRCA1 3'UTR reporter); silencing of TIAR strongly elevates BRCA1 protein levels.\",\n      \"method\": \"Polysome profiling, luciferase reporter with BRCA1 3'UTR, RNA immunoprecipitation, siRNA knockdown, subcellular fractionation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling plus reporter plus RIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25483082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In vivo PAR-CLIP of mouse liver TIAL1 identified Insig2 and ApoB as prominent TIAL1 target transcripts; TIAL1 influences their translation in hepatocytes; Tial1 mutant mice exhibit altered cholesterol synthesis, APOB secretion, and plasma cholesterol levels, placing TIAL1 in the negative feedback regulation of cholesterol biosynthesis.\",\n      \"method\": \"In vivo PAR-CLIP (viP-CLIP) in mouse liver, translation assay in hepatocytes, Tial1 mutant mice with cholesterol/APOB phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CLIP with functional validation in mouse knockout model showing metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"37296170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIAR binds the 5' stem-loop (ε) of HBV pregenomic RNA (pgRNA) and promotes HBV DNA replication; TIAR increases translation of the polymerase (Pol) while decreasing translation of core protein (Cp) from the same pgRNA template; HBV replication or Cp expression induces TIAR redistribution from nucleus to cytoplasm.\",\n      \"method\": \"RNA immunoprecipitation, pulldown assay, Ribo-seq, PRM-based mass spectrometry, loss- and gain-of-function genetic analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Ribo-seq and mass spectrometry for translational readout plus RIP/pulldown for binding, loss- and gain-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"37699883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pro-B cells, TIA1 and TIAL1 act redundantly as global splicing regulators controlling hundreds of mRNAs; they bind 5' splice sites for exon definition and splicing of DNA damage repair genes (including Chek2 and Rif1); in their absence, pro-B cells show exacerbated DNA damage, altered p53 expression, and increased cell death.\",\n      \"method\": \"Conditional double knockout in pro-B cells, RNA-seq, iCLIP, RT-PCR splicing validation, DNA damage markers (γH2AX), flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional double KO with CLIP, RNA-seq, and functional DNA damage readouts, multiple orthogonal methods\",\n      \"pmids\": [\"36543128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIA1 and TIAL1 are required for germinal center (GC) B cell survival and differentiation; they control Mcl1 mRNA translation to promote expression of the prosurvival molecule MCL1; TIA1/TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection, expansion, and differentiation into high-affinity antibody-producing clones.\",\n      \"method\": \"Conditional double knockout mice, GC B cell phenotyping by flow cytometry, polysome profiling for MCL1 translation, Western blot\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional double KO with polysome profiling demonstrating translational mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"37474714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TIAL1 directly interacts with the core Hippo pathway component SAV1 (protein-protein interaction), disrupting the MST1-SAV1 interaction, thereby suppressing Hippo signaling and activating YAP; this function is independent of TIAL1's RNA-binding activity, as RNA-binding-deficient mutants still interact with SAV1 and suppress Hippo; TIAL1 expression is upregulated by energy surplus and EGF.\",\n      \"method\": \"Co-immunoprecipitation, domain mutant analysis (RNA-binding deficient mutants), YAP activity reporter, MST1-SAV1 interaction assay, loss/gain-of-function in hepatocellular carcinoma cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with RNA-binding mutants and functional Hippo pathway readout, single lab, recently published with no replication yet\",\n      \"pmids\": [\"42032365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The first 23 nucleotides of the TIAR 5'UTR are both necessary and sufficient to confer resistance to SARS-CoV-2 Nsp1-mediated translation shutoff; the absence of guanosines within positions 10-18 downstream from the 5' end is a defining sequence feature (not secondary structure) shared between the SARS-CoV-2 leader and the TIAR 5'UTR that confers Nsp1 resistance.\",\n      \"method\": \"Reporter shutoff assays with 5'UTR truncation and mutation constructs in cells expressing Nsp1\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic reporter mutagenesis identifying necessary and sufficient sequence features, single lab\",\n      \"pmids\": [\"41407513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxia-induced lactylation of HMGB1 at K177 drives nuclear export of HMGB1 in a complex with TIAR, promoting stress granule formation in the cytosol; K177R mutation of HMGB1 completely blocks HMGB1-TIAR complex export and subsequent SG formation; other stressors (arsenite, heat shock) trigger TIAR nuclear export and SG assembly independently of HMGB1.\",\n      \"method\": \"Mass spectrometry of HMGB1 lactylation sites, K-to-R mutant transfection, co-immunoprecipitation of HMGB1-TIAR complex, immunofluorescence for SG formation\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identifying modification site plus functional mutant analysis, single lab, recently published\",\n      \"pmids\": [\"40788094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIAR (and TIA-1) bind SIRT1 pre-mRNA and regulate its alternative splicing; TIAL1 knockdown inhibits exon 8 exclusion (decreasing SIRT1-ΔExon8 levels), while HuR promotes exon 8 exclusion, revealing antagonistic regulation of SIRT1 splicing between these two RBPs.\",\n      \"method\": \"siRNA knockdown of TIA1/TIAL1 and HuR, RT-PCR for SIRT1 splice variants, reporter assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with splice variant quantification, single lab, two RNA-binding proteins compared\",\n      \"pmids\": [\"24566137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TIA-1 and TIAR binding sites on the WNV 3'(-)SL RNA were mapped to short AU sequences (UAAUU) in two internal loops; mutations that reduce TIAR/TIA-1 binding efficiency progressively decrease intracellular genomic RNA levels and virus production without affecting translation efficiency of mutant RNAs; several mutants rapidly reverted in vivo, indicating TIAR/TIA-1 interaction facilitates asymmetric amplification of genome RNA from the minus-strand template.\",\n      \"method\": \"Infectious clone mutagenesis, in vitro binding assays, plaque assays, intracellular RNA quantification, reversion analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic site-directed mutagenesis in infectious clone with multiple functional readouts correlating binding affinity with replication efficiency\",\n      \"pmids\": [\"18768985\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIAL1/TIAR is a multi-functional RNA-binding protein with three RRMs (RRM2 being the primary high-affinity binding domain for U-rich RNA and T-rich DNA, with the RRM2 C-terminal linker required for nanomolar affinity) that: (1) shuttles between nucleus and cytoplasm (import via RRM2/auxiliary domain in a Ran-GTP-dependent manner; export via RRM3 in a CRM1-independent manner, with hypoxic stress triggering HMGB1-lactylation-dependent cytoplasmic redistribution); (2) promotes assembly of stress granules downstream of eIF-2alpha phosphorylation; (3) represses translation of ARE-containing and C-rich-motif-containing mRNAs (including TNF-alpha, MYC, eIF4A, eIF4E, 5'TOP mRNAs, BRCA1, and MCL1) and facilitates translation of others (Insig2, ApoB, HBV polymerase); (4) activates inclusion of alternative exons with weak 5' splice sites followed by U-rich intronic sequences (covering ~15% of alternative cassette exons genome-wide), including autoregulatory cross-control of TIAR levels through TIA-1-induced NMD-coupled splicing; (5) functions at the G2/M checkpoint by sequestering CDK1 in nuclear G2/M transition granules under replication stress; (6) is essential for primordial germ cell survival, germinal center B cell responses (via MCL1 translation), and pro-B cell DNA repair splicing programs; and (7) can interact with viral RNAs (WNV, dengue, HBV) to facilitate replication, and with proteins (SAV1) in an RNA-binding-independent manner to suppress Hippo signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIAL1 (TIAR) is a multifunctional RNA-binding protein that couples cellular stress to post-transcriptional control of gene expression, acting as a nucleator of cytoplasmic stress granules, a translational repressor of specific mRNAs, and a sequence-specific regulator of alternative splicing [#0, #7, #10]. Its RNA/DNA recognition is built on three RRMs, of which RRM2 plus a short C-terminal linker constitutes the major high-affinity (nanomolar) module for U-rich RNA and T-rich single-stranded DNA, while RRM1 contributes DNA preference and RRM3 binds a broad RNA population and drives nuclear export [#2, #18, #20]. The two N-terminal domains adopt a flexible elongated conformation upon RNA binding, distinguishing TIAR's binding mode from related Hu proteins [#19]. In the cytoplasm, TIAR assembles stress granules downstream of eIF-2alpha phosphorylation and represses translation of ARE- and C-rich-motif-containing target mRNAs including TNF-alpha, MYC, the translation factors eIF4A/eIF4E, 5'TOP mRNAs, HIF-1alpha, and BRCA1, frequently in competition or partnership with HuR and AUF1 [#0, #1, #3, #6, #7, #15, #22, #25]. In the nucleus, TIAR activates inclusion of alternative cassette exons that carry weak 5' splice sites followed by U-rich intronic stretches—a mechanism covering roughly 15% of alternatively spliced exons genome-wide and including autoregulatory cross-control whereby TIA-1 drives an NMD-coupled TIAR splicing event to set TIAR levels [#9, #10, #21]. TIAR shuttles continuously between nucleus and cytoplasm, with import requiring RRM2/auxiliary regions in a Ran-GTP-dependent manner and CRM1-independent export via RRM3, and it redistributes to the cytoplasm under apoptotic and stress signals [#8, #14]. Through these activities TIAR is essential for primordial germ cell survival, governs a G2/M checkpoint by sequestering and attenuating CDK1 in nuclear G2/M transition granules under replication stress, and supports germinal-center B-cell survival via MCL1 translation and pro-B-cell DNA-repair splicing programs [#4, #23, #28, #29]. TIAR is additionally co-opted by viral RNAs to facilitate flavivirus (West Nile, dengue) genome amplification and HBV replication, and it suppresses Hippo signaling through an RNA-binding-independent protein interaction with SAV1 [#5, #17, #27, #30, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established which domain confers TIAR's RNA-binding specificity, defining RRM2 as the determinant of U-rich sequence recognition.\",\n      \"evidence\": \"SELEX from random RNA pools with domain deletion mutants and filter-binding affinity measurement\",\n      \"pmids\": [\"8576255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic contacts or the role of the C-terminal linker\", \"RRM1's apparent inability to bind RNA later contrasted with its DNA binding\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed that TIAR localization is stimulus-responsive, redistributing from nucleus to cytoplasm during apoptosis before DNA fragmentation.\",\n      \"evidence\": \"Immunofluorescence and fractionation during Fas-mediated apoptosis time course\",\n      \"pmids\": [\"7533298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the signal or transport machinery driving redistribution\", \"Functional consequence of cytoplasmic TIAR not mechanistically dissected here\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated an essential physiological requirement for TIAR in primordial germ cell survival via knockout phenotype.\",\n      \"evidence\": \"TIAR knockout mouse with embryo histology and ES cell proliferation assay\",\n      \"pmids\": [\"9482885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the mRNA targets responsible for PGC survival\", \"Molecular basis of the ES cell LIF-dependent proliferation defect unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed TIAR/TIA-1 downstream of eIF-2alpha phosphorylation as a nucleator of stress granule assembly and translational arrest.\",\n      \"evidence\": \"Phosphomimetic/nonphosphorylatable eIF-2alpha mutants and dominant-negative TIA-1, fluorescence microscopy\",\n      \"pmids\": [\"10613902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which RNAs are recruited into granules\", \"Mechanism of self-aggregation/granule nucleation not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected TIAR to a defined cytokine mRNA target by showing ARE-dependent binding to TNF-alpha mRNA.\",\n      \"evidence\": \"EMSA and immunoprecipitation in macrophage cytoplasmic fractions\",\n      \"pmids\": [\"9890998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional translational repression inferred, not directly demonstrated in this study\", \"Single lab without reciprocal validation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined TIAR's splicing-activator mechanism: recognition of U-rich intronic stretches downstream of weak 5' splice sites, including autoregulatory exons.\",\n      \"evidence\": \"In vitro splicing assays and minigene reporters with U-rich deletion mutagenesis\",\n      \"pmids\": [\"11514562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish genome-wide scope at this stage\", \"snRNP recruitment mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed that TIAR is hijacked by a viral RNA element, binding the WNV minus-strand 3' stem-loop and supporting replication.\",\n      \"evidence\": \"RNA affinity purification, Kd measurement, and virus growth in knockout/reconstituted cells\",\n      \"pmids\": [\"12414941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which binding promotes replication not yet defined here\", \"Distinction between TIAR and TIA-1 roles unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established a self-regulatory circuit whereby TIA-1 controls TIAR abundance through splicing-coupled NMD.\",\n      \"evidence\": \"Conditional gene disruption in DT40 cells with RT-PCR, cycloheximide NMD assay, and rescue\",\n      \"pmids\": [\"12533540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the full set of co-regulated targets\", \"Physiological setting of autoregulation in mammalian tissues unaddressed here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed mechanistic interplay between TIAR and the spliceosome, with synergistic U6 snRNA recruitment at a pseudo 5' splice site enhancer.\",\n      \"evidence\": \"UV cross-linking, EMSA, dominant-negative TIAR, and minigene reporters with snRNA interaction analysis\",\n      \"pmids\": [\"12917321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the synergistic complex\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified translation factor mRNAs and c-Myc as direct TIAR-repressed targets mediating UVC-induced translational shutdown.\",\n      \"evidence\": \"RIP, reporters, siRNA rescue, and polysome profiling under UVC stress\",\n      \"pmids\": [\"16537914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether repression occurs in stress granules or by direct initiation block\", \"Selectivity rules among 3'UTR targets unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated competitive control of MYC mRNA between TIAR and AUF1, linking TIAR abundance inversely to proliferation.\",\n      \"evidence\": \"RIP, reporters, siRNA/overexpression, and proliferation assays with genetic epistasis\",\n      \"pmids\": [\"17486099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the reciprocal binding competition not structurally defined\", \"Generality across other ARE targets not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded TIAR's binding repertoire beyond U-rich motifs to a C-rich stem-loop and showed stress-induced dissociation derepresses targets.\",\n      \"evidence\": \"RIP-chip, SPR binding, and luciferase reporters under UVC stress\",\n      \"pmids\": [\"17682065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal triggering target release from TIAR under stress not identified\", \"Single-lab characterization of C-rich binding mode\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Quantified the genome-wide scope of TIA1/TIAL1-dependent splicing, attributing ~15% of cassette exon regulation to U-rich intronic motifs.\",\n      \"evidence\": \"Double siRNA knockdown with splicing microarray, RT-PCR validation, and motif analysis\",\n      \"pmids\": [\"18456862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy partitioning between TIA1 and TIAL1 not resolved per-target\", \"Tissue-specific splicing programs not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the 5'TOP mRNA arrest mechanism, showing TIAR assembles on 5' ends to block initiation under amino acid starvation via GCN2/mTOR signaling.\",\n      \"evidence\": \"RIP, polysome profiling, siRNA, reporters, and stress granule imaging\",\n      \"pmids\": [\"21979918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contact between TIAR and 5'TOP elements not structurally mapped\", \"Relationship to canonical TOP regulators left open\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural insight distinguishing TIAR from Hu proteins, with a flexible elongated conformation and unusually strong DNA binding.\",\n      \"evidence\": \"SPR and SAXS with DNA/RNA variant comparison\",\n      \"pmids\": [\"21233170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution complex structure\", \"Functional importance of the elongated conformation in cells untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Pinpointed the minimal high-affinity module as RRM2 plus a six-residue C-terminal linker, identifying residues engaging AU-rich RNA.\",\n      \"evidence\": \"SPR and NMR with domain truncations\",\n      \"pmids\": [\"23603827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linker's structural role not fully visualized in a complex\", \"How RRM1 and RRM3 cooperate with RRM2 in vivo unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a nuclear G2/M checkpoint function in which TIAR sequesters and attenuates CDK1 in transition granules under replication stress.\",\n      \"evidence\": \"siRNA, immunofluorescence, flow cytometry, CDK1 activity assay, and epistasis with Cdc25B/CDK1 inhibition\",\n      \"pmids\": [\"30538118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RNA binding is required for GMG assembly not resolved\", \"Composition and biogenesis of GMGs only partially defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a developmental splicing program in which TIA1/TIAL1 redundantly control DNA-repair gene splicing to protect pro-B cells.\",\n      \"evidence\": \"Conditional double knockout with iCLIP, RNA-seq, splicing RT-PCR, and DNA damage readouts\",\n      \"pmids\": [\"36543128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of Chek2 vs Rif1 mis-splicing to the phenotype not isolated\", \"Whether translational targets also contribute unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated an in vivo metabolic role, with hepatic TIAL1 controlling Insig2/ApoB translation and cholesterol homeostasis.\",\n      \"evidence\": \"In vivo PAR-CLIP in mouse liver, hepatocyte translation assays, and Tial1 mutant cholesterol/APOB phenotyping\",\n      \"pmids\": [\"37296170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether translation is enhanced or repressed per target not uniformly resolved\", \"Mechanistic link to the cholesterol feedback loop only correlative\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TIAR differentially controls translation of two proteins from one HBV pgRNA template via 5' stem-loop binding to promote replication.\",\n      \"evidence\": \"RIP/pulldown, Ribo-seq, PRM mass spectrometry, and loss/gain-of-function\",\n      \"pmids\": [\"37699883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism producing opposite effects on Pol vs Cp not resolved\", \"Trigger for TIAR nuclear-to-cytoplasm redistribution during infection unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MCL1 mRNA translation as the TIA1/TIAL1-dependent pathway sustaining germinal center B-cell survival and selection.\",\n      \"evidence\": \"Conditional double knockout mice with GC phenotyping and polysome profiling\",\n      \"pmids\": [\"37474714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MCL1 is a direct binding target shown by CLIP not established here\", \"Contribution of splicing vs translational control to the phenotype not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an RNA-binding-independent function: TIAL1 binds SAV1 to disrupt MST1-SAV1 and suppress Hippo signaling, activating YAP.\",\n      \"evidence\": \"Co-IP, RNA-binding-deficient mutants, YAP reporter, and MST1-SAV1 interaction assays in HCC cells\",\n      \"pmids\": [\"42032365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recently published without independent replication\", \"Structural basis of the TIAL1-SAV1 interaction undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked hypoxia metabolism to TIAR trafficking via HMGB1 K177 lactylation driving HMGB1-TIAR co-export and stress granule formation.\",\n      \"evidence\": \"Mass spectrometry of lactylation sites, K177R mutant, co-IP, and SG imaging\",\n      \"pmids\": [\"40788094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab and recently published\", \"How the HMGB1-TIAR complex nucleates SGs mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a sequence determinant in the TIAR 5'UTR that confers resistance to SARS-CoV-2 Nsp1 translation shutoff.\",\n      \"evidence\": \"Reporter shutoff assays with 5'UTR truncation/mutation constructs\",\n      \"pmids\": [\"41407513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the cellular consequence of TIAR escaping shutoff\", \"Mechanism by which guanosine absence confers resistance not biochemically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TIAR's distinct activities—splicing activation, translational repression, granule nucleation, and RNA-binding-independent signaling—are coordinated and switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking domain conformation to functional mode switching\", \"Signal-specific rules governing TIAR localization and target selection undefined\", \"No high-resolution structure of TIAR bound to a physiological target\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 15, 19, 20, 26, 28]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [18, 19, 20]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [3, 6, 7, 22, 25, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 10, 11, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 14, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 8, 17]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 14, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 10, 21, 28]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 3, 22, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 7, 25, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 17, 27, 34]}\n    ],\n    \"complexes\": [\n      \"stress granule\",\n      \"G2/M transition granules (GMGs)\"\n    ],\n    \"partners\": [\n      \"TIA1\",\n      \"HuR\",\n      \"AUF1\",\n      \"hnRNP U\",\n      \"CDK1\",\n      \"SAV1\",\n      \"HMGB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}