{"gene":"TIAL1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1999,"finding":"Assembly of TIA-1/TIAR-positive stress granules (SGs) is initiated downstream of eIF-2α phosphorylation; a phosphomimetic eIF-2α mutant (S51D) induces SG assembly, a non-phosphorylatable mutant (S51A) prevents it, and a TIAR mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation, placing TIAR downstream of eIF-2α in the pathway that sequesters untranslated mRNAs.","method":"Phosphomimetic/non-phosphorylatable eIF-2α mutants, transdominant-negative TIAR mutant overexpression, fluorescence microscopy of SG assembly","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic constructs in a single study; foundational paper replicated broadly","pmids":["10613902"],"is_preprint":false},{"year":1996,"finding":"RRM2 of both TIA-1 and TIAR is the domain responsible for high-affinity, specific binding to uridylate-rich RNA sequences; RRM1 does not bind cellular RNA in affinity-precipitation assays, while RRM3 binds a broad population of cellular RNAs; affinity increases when RRM2 is expressed together with RRM1 and RRM3.","method":"In vitro SELEX, filter-binding assays with individual recombinant RRM domains, affinity precipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays with systematic domain-deletion mutants and Kd measurements","pmids":["8576255"],"is_preprint":false},{"year":1995,"finding":"TIAR is concentrated in the nucleus of hematopoietic and non-hematopoietic cells and translocates from the nucleus to the cytoplasm within 30 min of Fas ligation, preceding the onset of DNA fragmentation during Fas-mediated apoptosis; this redistribution is not observed during mitogenic activation.","method":"Immunofluorescence microscopy, subcellular fractionation, Fas ligation time-course","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional context (apoptosis timing), replicated in subsequent studies","pmids":["7533298"],"is_preprint":false},{"year":1999,"finding":"TIAR binds directly to the AU-rich element (ARE) of TNF-α mRNA (requiring clustered AUUUA pentamers) in the cytoplasm of macrophages, implicating it in translational repression of TNF-α.","method":"RNA-protein complex identification by competition gel mobility shift and UV cross-linking, cytoplasmic localization by fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct identification of TIAR in complex with ARE; corroborated by subsequent studies on TNF translation","pmids":["9890998"],"is_preprint":false},{"year":1998,"finding":"TIAR is essential for primordial germ cell (PGC) survival and development; TIAR-knockout mice show severely reduced PGC numbers by E11.5 and complete absence by E13.5, and TIAR-deficient ES cells fail to proliferate without exogenous LIF, consistent with a role for TIAR in regulating a survival/proliferation factor.","method":"Knockout mouse (gene targeting), embryo staging, methylcellulose ES cell proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific developmental phenotype and cellular assay","pmids":["9482885"],"is_preprint":false},{"year":2001,"finding":"TIAR (like TIA-1) activates splicing of alternative exons with weak 5' splice sites that are followed by U-rich intronic sequences on the TIA-1 and TIAR pre-mRNAs themselves, demonstrating autoregulatory splicing; in vitro splicing assays showed direct activation requires a downstream U-rich stretch of ≥10 residues.","method":"Overexpression in cells, in vitro splicing assays, deletion of U-rich stretches, cryptic splice-site analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro splicing reconstitution plus in vivo overexpression with U-rich element mutagenesis","pmids":["11514562"],"is_preprint":false},{"year":2002,"finding":"TIAR (p42) was purified by RNA affinity chromatography and identified by peptide sequencing as a specific binding partner of the West Nile virus 3'-terminal minus-strand stem-loop (WNV 3'(-)SL) RNA; binding maps to RRM2 with Kd ~1.5×10⁻⁸ M (10-fold tighter than TIA-1 RRM2); WNV growth is less efficient in TIAR-knockout cells and is partially rescued by TIAR reconstitution.","method":"RNA affinity column purification, peptide sequencing, competition gel-shift assays with recombinant proteins, TIAR knockout cell lines, viral reconstitution","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — protein purification and direct Kd measurement; functional confirmation by KO and rescue","pmids":["12414941"],"is_preprint":false},{"year":2006,"finding":"TIAR selectively binds the 3'-UTRs of mRNAs encoding translation factors (eIF4A, eIF4E, eEF1B) and c-Myc, potently suppressing their translation particularly in response to UVC irradiation; silencing TIAR significantly relieves UVC-induced global translational arrest.","method":"RNP immunoprecipitation, polysome profiling, TIAR siRNA knockdown, reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — RIP combined with knockdown and functional translational readout","pmids":["16537914"],"is_preprint":false},{"year":2007,"finding":"AUF1 and TIAR competitively bind the ARE of MYC mRNA to regulate its translation: MYC translation and cell proliferation are proportional to AUF1 abundance and inversely proportional to TIAR abundance; altering one protein's mRNA association reciprocally affects the other's; genetic experiments place both in a MYC-dependent proliferation pathway.","method":"ARE-binding competition assays, polysome profiling, siRNA knockdown, genetic epistasis (MYC-dependent pathway)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic epistasis and competitive binding","pmids":["17486099"],"is_preprint":false},{"year":2011,"finding":"Upon amino acid starvation, TIAR assembles onto the 5' end of 5'TOP mRNAs and arrests their translation at the initiation step, causing polysome release and accumulation in stress granules; this requires GCN2 kinase activation and mTOR inactivation.","method":"Polysome profiling, RIP, siRNA knockdown, stress granule imaging, pharmacological inhibition of GCN2 and mTOR","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — polysome profiling plus pathway-level genetic dissection with multiple orthogonal approaches","pmids":["21979918"],"is_preprint":false},{"year":2008,"finding":"Simultaneous knockdown of TIA1 and TIAL1 causes increased skipping of 88% of alternatively spliced exons flanked by U-rich intronic motifs downstream of 5' splice sites, but does not affect exons lacking such motifs, demonstrating a genome-wide role for TIAL1 in promoting exon inclusion via U-rich intronic elements.","method":"siRNA knockdown of TIA1/TIAL1, splicing-sensitive microarrays, RT-PCR validation, U-rich motif enrichment analysis","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 — genome-scale knockdown with RT-PCR validation; orthogonal bioinformatics confirms motif specificity","pmids":["18456862"],"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 drive nuclear accumulation, while RRM3 mediates nuclear export; nuclear import is Ran-GTP-dependent, whereas export is Ran-GTP- and CRM1-independent; both RRMs function through their RNA-binding capacity.","method":"GFP-tagged deletion/point mutants, Ran-GTP depletion, CRM1 inhibition (leptomycin B), live-cell imaging, FRAP-like shuttling assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — systematic domain mutagenesis with RNP-motif point mutants and multiple pharmacological controls","pmids":["16278295"],"is_preprint":false},{"year":2006,"finding":"Fas-activated serine/threonine kinase (FAST K) phosphorylates TIA-1/TIAR and thereby enhances Fas exon 6 inclusion (pro-apoptotic isoform); depletion of FAST K causes exon 6 skipping, overexpression promotes inclusion, and this effect requires both TIA-1/TIAR and a U-rich intronic enhancer downstream of exon 6; in vitro, FAST K phosphorylation of TIA-1 enhances U1 snRNP recruitment without increasing pre-mRNA binding.","method":"FAST K depletion/overexpression, TIA-1/TIAR siRNA, minigene splicing reporters with U-rich enhancer mutations, in vitro phosphorylation and U1 snRNP recruitment assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation assay combined with in vivo epistasis and mutational analysis","pmids":["17135269"],"is_preprint":false},{"year":2003,"finding":"TIAR binds a U-tract sequence downstream of a pseudo 5' splice site in the calcitonin/CGRP intron enhancer and promotes inclusion of the upstream alternative 3'-terminal exon; this binding depends on U1 and U6 snRNA interactions with the pseudo 5' splice site, and TIAR binding in turn promotes U6 snRNA binding, revealing a synergistic relationship.","method":"RNA affinity pull-down, EMSA, overexpression of dominant-negative TIAR, in vivo splicing reporters, snRNA binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple binding and functional assays with dominant-negative approach","pmids":["12917321"],"is_preprint":false},{"year":2007,"finding":"TIAR associates with subsets of mRNAs bearing a cytosine-rich (~28-32 nt) stem-loop motif in addition to U-rich sequences; in vitro SPR confirmed TIAR (RRM1-2 and RRM1-3) binding to this C-rich motif; insertion of the motif into a reporter strongly suppressed translation; after UVC stress, target mRNAs dissociate from TIAR and encoded proteins increase in a TIAR-dependent manner.","method":"RNP immunoprecipitation + microarray, surface plasmon resonance, reporter translational assays, UVC stress dissociation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding with SPR plus in vivo reporter validation and stress-response dissociation","pmids":["17682065"],"is_preprint":false},{"year":2005,"finding":"TIAR binds single-stranded, thymidine/uridine-rich DNA with ~6-fold higher affinity than RNA (Kd ~1.6×10⁻⁹ M vs 9.4×10⁻⁹ M for RNA); the high-affinity DNA-binding site maps to RRM2 (overlapping the RNA-binding site); RRM1 alone also binds DNA; active transcription through the binding site can displace TIAR from ssDNA.","method":"UV cross-linking, EMSA, TIAR domain truncations, filter-binding affinity measurements","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays with Kd determination and systematic domain mapping","pmids":["16091628"],"is_preprint":false},{"year":2011,"finding":"TIAR binds both U-rich and AU-rich RNA with nanomolar affinity (higher affinity for U-rich RNA due to faster association); TIAR can also bind deoxy-oligonucleotides with nanomolar affinity whereas HuR affinity for DNA is micromolar; SAXS of TIAR RRM1-2 in complex with RNA shows a flexible, elongated shape distinct from the compact structure of Hu proteins, indicating a different binding mode.","method":"Surface plasmon resonance (SPR), SAXS, comparative binding studies with U-rich RNA and DNA","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — SPR quantification plus structural SAXS analysis with functional comparison","pmids":["21233170"],"is_preprint":false},{"year":2013,"finding":"RRM2 together with its C-terminal six-amino-acid linker extension is the major high-affinity (nM) binding domain for both U-rich RNA and T-rich DNA; RRM1 alone preferentially binds DNA over RNA; NMR spectroscopy identified the specific residues in RRM2+extension involved in RNA contact.","method":"SPR, NMR spectroscopy, domain-specific binding assays","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structural validation combined with quantitative SPR binding","pmids":["23603827"],"is_preprint":false},{"year":2003,"finding":"HuR, TIA-1, TIAR, and hnRNP U form a multimeric protein complex on the first 60 nucleotides of the COX-2 mRNA 3'-UTR (containing AUUUA repeats); this complex represses expression, and IL-1β stimulation increases cytosolic HuR binding and COX-2 mRNA levels.","method":"EMSA, immunoprecipitation of complex members, reporter gene assay with 60-nt 3'-UTR insert","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab EMSA/IP; functional reporter confirms regulatory role","pmids":["12855701"],"is_preprint":false},{"year":2002,"finding":"TIAR binds the AU-rich sequence (5'-UUUUAAAUUUU) in Sendai virus trailer RNA; sequestration of TIAR by this viral RNA has an anti-apoptotic effect; transgenic overexpression of TIAR during SeV infection promotes apoptosis and reverses the anti-apoptotic effect of trailer RNA expression.","method":"In vitro binding assays, transgenic TIAR overexpression, apoptosis assays in mixed infections","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding plus functional overexpression with apoptosis readout","pmids":["12356730"],"is_preprint":false},{"year":2007,"finding":"In West Nile virus- and dengue virus-infected cells, TIAR and TIA-1 co-localize with viral replication complex components (dsRNA, NS3) in perinuclear regions; TIAR relocates coincident with peak RNA synthesis, and this interaction suppresses stress granule formation and progressively reduces processing body numbers.","method":"Immunofluorescence co-localization, kinetic analysis of TIAR redistribution vs. RNA synthesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 — co-localization imaging without biochemical co-IP; functional SG suppression confirmed","pmids":["17502609"],"is_preprint":false},{"year":2008,"finding":"TIA-1/TIAR binding sites on the WNV 3'(-)SL RNA were mapped to short AU sequences (UAAUU) in two internal stem-loop loops; mutations abolishing TIAR/TIA-1 binding in infectious clones proportionally reduce viral genomic RNA amplification (not translation), with lethal mutations reverting in vivo, indicating these proteins facilitate asymmetric genome amplification from the minus-strand template.","method":"Infectious clone mutagenesis, in vitro binding assays, plaque assays, intracellular RNA quantification","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis in infectious clone correlated with quantitative binding and replication data","pmids":["18768985"],"is_preprint":false},{"year":2002,"finding":"An alternatively spliced form of TIAR (containing a 17-amino-acid insert) is expressed in human but not rat cells and is required for species-dependent translational repression of HMMP13 mRNA; transient expression of the insert reverses silencing in human cells, and co-transfection of this isoform suppresses HMMP13 protein expression in Rat2 cells.","method":"Reporter assays, transient expression of TIAR isoform and insert peptide, species comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — isoform-specific functional assay with cross-species rescue","pmids":["12426321"],"is_preprint":false},{"year":2018,"finding":"TIAR accumulates in nuclear foci (G2/M transition granules, GMGs) during late G2/prophase under replication stress; GMGs contain CDK1, and TIAR retains CDK1 in these granules to attenuate its activity; depletion of TIAR accelerates mitotic entry and causes chromosomal instability that is rescued by co-depletion of Cdc25B or CDK1 inhibition.","method":"Immunofluorescence time-course, TIAR siRNA, genetic epistasis with Cdc25B/CDK1, CDK1 activity assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — clean KD with specific mitotic phenotype, genetic epistasis with CDK1/Cdc25B, and CDK1 retention mechanism","pmids":["30538118"],"is_preprint":false},{"year":2014,"finding":"In BCR-ABL1-positive CML cells, ER stress promotes cytosolic localization of TIAR, its binding to BRCA1 mRNA 3'-UTR, and formation of a TIAR-HuR complex; TIAR negatively regulates BRCA1 mRNA translation (demonstrated by polysome profiling and luciferase-BRCA1 3'-UTR reporter), and TIAR silencing strongly elevates BRCA1 protein levels.","method":"Polysome profiling, luciferase-3'UTR reporter, RNA immunoprecipitation, TIAR siRNA knockdown, subcellular fractionation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods showing TIAR-dependent translational repression","pmids":["25483082"],"is_preprint":false},{"year":2010,"finding":"Under acute/severe hypoxia, TIAR and TIA-1 co-aggregate into stress granules (co-staining with eIF3η); HIF-1α expression is blocked in cells displaying TIAR/TIA-1 granules; TIAR/TIA-1 silencing upregulates HIF-1α; ARE in HIF-1α 3'-UTR drives TIAR-dependent translational suppression in reporter assays.","method":"Immunofluorescence, siRNA knockdown, HIF-1α reporter with 3'-UTR ARE, western blot","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter and knockdown confirm mechanism but single laboratory","pmids":["20980400"],"is_preprint":false},{"year":2016,"finding":"LncRNA MT1JP interacts with TIAR (RNA-binding protein) to enhance translation of p53 mRNA; MT1JP down-regulation reduces p53 protein without affecting mRNA, and this effect is mediated through TIAR.","method":"RNA pull-down, RIP, polysome analysis, siRNA knockdown, luciferase reporter","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — single lab with multiple assays; indirect evidence for TIAR as effector","pmids":["26909858"],"is_preprint":false},{"year":2023,"finding":"In vivo PAR-CLIP (viP-CLIP) in mouse liver identified Insig2 and ApoB mRNAs as prominent TIAL1 targets; TIAL1 influences their translation in hepatocytes; Tial1 mutant mice exhibit altered cholesterol synthesis, APOB secretion, and plasma cholesterol levels, placing TIAL1 in negative feedback regulation of cholesterol biosynthesis.","method":"In vivo PAR-CLIP in liver tissue, translation assays in hepatocytes, Tial1 mutant mice with cholesterol phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo CLIP combined with KO mouse metabolic phenotype and hepatocyte translational assays","pmids":["37296170"],"is_preprint":false},{"year":2023,"finding":"TIAR binds the 5' stem-loop (ε) of HBV pregenomic RNA (pgRNA) and differentially regulates translation: TIAR increases Pol translation while decreasing Cp translation from the same pgRNA; HBV replication or Cp expression induces TIAR nuclear-to-cytoplasmic redistribution, creating a feedback loop that balances Cp and Pol levels.","method":"Ribo-seq, PRM mass spectrometry, RIP, RNA pulldown, Cp/Pol expression measurement, TIAR subcellular redistribution imaging","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1-2 — Ribo-seq and proteomics quantify translational shift; direct binding to 5'ε confirmed","pmids":["37699883"],"is_preprint":false},{"year":2022,"finding":"TIA1 and TIAL1 act as global splicing regulators in pro-B cells, binding 5' splice sites for exon definition to control expression of DNA damage sensors including Chek2 and Rif1; double knockout leads to exacerbated DNA damage, altered p53, and increased cell death.","method":"Conditional knockout, RNA-seq, CLIP-seq (binding at 5' splice sites), western blot for DNA damage markers","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with genome-wide splicing readout and mechanistic binding data","pmids":["36543128"],"is_preprint":false},{"year":2023,"finding":"TIA1 and TIAL1 are required for germinal center B cell positive selection and differentiation; they control the translational identity of dark- and light-zone GC B cells and enable timely expression of the pro-survival molecule MCL1.","method":"Conditional knockout in B cells, germinal center assays, polysome profiling for MCL1, flow cytometry","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with specific GC phenotype and mechanistic translational readout","pmids":["37474714"],"is_preprint":false},{"year":2019,"finding":"C. elegans TIAR-2 undergoes liquid-liquid phase separation via its C-terminal prion-like domain (PrLD) and forms liquid-like granules in vivo that inhibit axon regeneration cell-autonomously; axon injury transiently increases granule number; non-phosphorylatable TIAR-2 variants fail to form granules and cannot inhibit regeneration; tyrosine residues in the PrLD are important for granule formation.","method":"In vitro phase separation assay, live imaging of granule dynamics (liquid-like properties), PrLD deletion/tyrosine mutants, phosphorylation mutants, axon regeneration assays in C. elegans","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of phase separation plus in vivo mutagenesis with specific regeneration phenotype","pmids":["31378567"],"is_preprint":false},{"year":2025,"finding":"TIAL1 directly interacts with the Hippo pathway component SAV1, disrupting the MST1-SAV1 interaction and thereby suppressing Hippo signaling to activate YAP; this function is independent of TIAL1's RNA-binding activity; extracellular stimuli (energy surplus, EGF) upregulate TIAL1 expression to modulate this pathway.","method":"Co-immunoprecipitation, RNA-binding-deficient TIAL1 mutants, MST1-SAV1 interaction assays, YAP activity reporters","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and RNA-binding-independent mutants; single-lab study","pmids":["42032365"],"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 NMD, revealing a TIA-1-mediated autoregulatory loop that controls TIAR expression at the splicing level.","method":"Gene targeting in DT40 cells, RT-PCR, cycloheximide treatment (NMD assay), TIA-1 expression rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in KO cells with NMD validation","pmids":["12533540"],"is_preprint":false},{"year":2025,"finding":"The first 23 nucleotides of the TIAR 5' UTR are necessary and sufficient to confer resistance to SARS-CoV-2 Nsp1-mediated host translational shutoff; the absence of guanosines within positions 10-18 from the 5' end is the defining sequence feature shared between TIAR 5' UTR and the viral leader that confers Nsp1 resistance.","method":"Reporter shutoff assays with TIAR 5' UTR deletion/substitution mutants, sequence comparison with SARS-CoV-2 leader","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutagenesis in reporter assay; single lab","pmids":["41407513"],"is_preprint":false},{"year":2025,"finding":"Hypoxia-induced lactylation of HMGB1 at K177 drives its nuclear export in a complex with TIAR, promoting stress granule formation in the cytosol; K177R mutation blocks this HMGB1-TIAR complex export and subsequent SG assembly; other stressors (arsenite, heat shock) trigger TIAR nuclear export and SG assembly independently of HMGB1.","method":"Mass spectrometry for lactylation sites, K→R mutagenesis, co-IP of HMGB1-TIAR complex, immunofluorescence of SG formation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — PTM-specific mutagenesis with Co-IP and functional SG readout; single-lab study","pmids":["40788094"],"is_preprint":false},{"year":2021,"finding":"PHAROH lncRNA sequesters TIAR via a 71-nt hairpin within PHAROH (identified by RNA-antisense pulldown), preventing TIAR from repressing MYC translation; PHAROH knockout decreases MYC protein without affecting mRNA.","method":"RNA-antisense pulldown, MYC protein/mRNA measurement in PHAROH KO cells, rescue by PHAROH re-expression","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding identified by pulldown; MYC translational effect validated in KO","pmids":["34002693"],"is_preprint":false}],"current_model":"TIAL1 (TIAR) is an RNA-binding protein with three RRM domains (RRM2 being the primary high-affinity binding domain for U-rich and C-rich RNA/ssDNA sequences) that operates at multiple post-transcriptional levels: it represses translation of specific mRNAs (including 5'TOP mRNAs, translation factors, MYC, BRCA1, HIF-1α) by binding their 3'-UTRs, promotes inclusion of alternative exons with weak 5' splice sites flanked by U-rich intronic sequences, assembles into cytoplasmic stress granules downstream of eIF-2α phosphorylation to sequester untranslated mRNAs during stress, undergoes regulated nuclear-cytoplasmic shuttling (nuclear import via Ran-GTP/RRM2; export via RRM3), facilitates flavivirus genome RNA amplification by binding viral minus-strand RNA, restrains CDK1 activity during the G2/M checkpoint by sequestering it in nuclear G2/M transition granules, and can act through an RNA-binding-independent mechanism by interacting with SAV1 to suppress Hippo signaling."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that TIAR is a predominantly nuclear protein that undergoes regulated nuclear-to-cytoplasmic redistribution during apoptosis resolved where and when TIAR acts, linking its subcellular dynamics to cell-death signaling.","evidence":"Immunofluorescence and subcellular fractionation during Fas-ligation time-course in hematopoietic cells","pmids":["7533298"],"confidence":"High","gaps":["Mechanism of nuclear export during apoptosis not defined","Whether redistribution is required for apoptosis execution not tested"]},{"year":1996,"claim":"Mapping high-affinity U-rich RNA binding to RRM2 (with cooperative contributions from RRM1 and RRM3) defined the molecular basis for TIAR target recognition, enabling all subsequent studies of its RNA-binding specificity.","evidence":"SELEX, filter-binding, and affinity precipitation with individual recombinant RRM domains","pmids":["8576255"],"confidence":"High","gaps":["Structural basis of RRM2 selectivity not yet resolved","In vivo target spectrum not addressed"]},{"year":1998,"claim":"Demonstrating that TIAR-knockout mice lose primordial germ cells and that TIAR-deficient ES cells require exogenous LIF for proliferation established TIAR as essential for cell survival and germ cell development.","evidence":"Gene-targeted knockout mice with embryonic staging; ES cell proliferation assay in methylcellulose","pmids":["9482885"],"confidence":"High","gaps":["Specific mRNA targets mediating PGC survival not identified","Redundancy with TIA-1 in vivo not fully dissected"]},{"year":1999,"claim":"Placing TIAR downstream of eIF2α phosphorylation in stress granule assembly provided the first mechanistic framework for how cells sequester untranslated mRNAs during stress, and showing that TIAR also binds TNF-α ARE linked it to cytokine translational control.","evidence":"Phosphomimetic/non-phosphorylatable eIF2α mutants with SG imaging; UV cross-linking and gel-shift with TNF-α ARE","pmids":["10613902","9890998"],"confidence":"High","gaps":["How TIAR nucleates SG condensation mechanistically was unknown","Relative contributions of TIA-1 vs TIAR to SG nucleation not separated"]},{"year":2001,"claim":"Showing that TIAR activates inclusion of alternative exons with weak 5′ splice sites by binding downstream U-rich intronic sequences—including autoregulatory exons in its own pre-mRNA—established TIAR as a sequence-specific splicing activator.","evidence":"In vitro splicing reconstitution with U-rich element deletions; in vivo overexpression with minigene reporters","pmids":["11514562"],"confidence":"High","gaps":["How TIAR promotes U1 snRNP recruitment mechanistically was unclear","Genome-wide scope of splicing regulation not yet measured"]},{"year":2002,"claim":"Identification of TIAR as a high-affinity binding partner of the WNV minus-strand 3′ stem-loop, with reduced viral growth in TIAR-KO cells, revealed an unexpected role for a host RNA-binding protein in flavivirus genome amplification.","evidence":"RNA affinity purification, peptide sequencing, Kd measurement, TIAR-KO cell viral growth and rescue","pmids":["12414941"],"confidence":"High","gaps":["Precise mechanism by which TIAR facilitates minus-to-plus strand synthesis not defined","Applicability to other flaviviruses not yet tested"]},{"year":2005,"claim":"Defining that TIAR continuously shuttles between nucleus and cytoplasm—with RRM2 driving Ran-GTP-dependent nuclear import and RRM3 mediating CRM1-independent export—explained how TIAR can function in both nuclear splicing and cytoplasmic translational control, and revealing high-affinity ssDNA binding expanded the repertoire of potential TIAR substrates.","evidence":"GFP-domain mutants with Ran depletion and leptomycin B treatment; UV cross-linking and EMSA with ssDNA Kd measurements","pmids":["16278295","16091628"],"confidence":"High","gaps":["Physiological relevance of DNA binding in vivo not demonstrated","Export receptor/adaptor identity unknown"]},{"year":2006,"claim":"Demonstrating that TIAR represses translation of mRNAs encoding translation factors and c-Myc via 3′-UTR binding, and that FASTK phosphorylation of TIA-1/TIAR enhances U1 snRNP recruitment for Fas exon 6 splicing, revealed dual regulatory outputs (translational repression and splicing activation) modulated by upstream kinase signaling.","evidence":"RNP-IP with polysome profiling and siRNA knockdown; FASTK phosphorylation assays with minigene splicing reporters","pmids":["16537914","17135269"],"confidence":"High","gaps":["Full kinase network regulating TIAR not mapped","Whether FASTK also regulates TIAR's translational function not tested"]},{"year":2007,"claim":"Discovery that TIAR binds a C-rich stem-loop motif in addition to U-rich sequences, and that AUF1 and TIAR competitively regulate MYC mRNA translation, broadened the RNA target code and revealed combinatorial control of specific transcripts.","evidence":"RNP-IP/microarray with SPR validation for C-rich motif; competitive ARE-binding and polysome profiling for MYC regulation","pmids":["17682065","17486099"],"confidence":"High","gaps":["Structural basis for C-rich motif recognition not determined","How the AUF1-TIAR balance is regulated upstream not known"]},{"year":2008,"claim":"Genome-wide splicing analysis confirmed that TIA1/TIAL1 control ~88% of alternative exons flanked by downstream U-rich motifs, and infectious-clone mutagenesis mapped the precise TIAR-binding sites on WNV minus-strand RNA required for viral genome amplification.","evidence":"Splicing-sensitive microarray after TIA1/TIAL1 knockdown; WNV infectious clone mutagenesis with binding and replication assays","pmids":["18456862","18768985"],"confidence":"High","gaps":["How TIAR binding promotes asymmetric replication mechanistically not resolved","Redundancy between TIA-1 and TIAR in splicing regulation not fully dissected"]},{"year":2011,"claim":"Showing that TIAR assembles onto 5′TOP mRNAs during amino acid starvation downstream of GCN2 activation and mTOR inactivation placed TIAR in a nutrient-sensing translational repression pathway, and biophysical characterization revealed that TIAR RRM1-2 adopts an elongated conformation distinct from HuR, explaining differential RNA/DNA binding modes.","evidence":"Polysome profiling with RIP under amino acid starvation, GCN2/mTOR inhibition; SPR and SAXS structural analysis","pmids":["21979918","21233170"],"confidence":"High","gaps":["How TIAR recognizes 5′TOP sequences specifically vs general U-rich elements not clarified","Whether elongated conformation is altered by post-translational modifications unknown"]},{"year":2013,"claim":"NMR mapping of the RNA-contacting residues in RRM2 plus its C-terminal six-amino-acid linker provided the first atomic-level view of TIAR's primary RNA-binding surface.","evidence":"NMR spectroscopy combined with SPR binding of domain-specific constructs","pmids":["23603827"],"confidence":"High","gaps":["No high-resolution co-crystal structure of RRM2-RNA complex","How RRM1 and RRM3 cooperate structurally with RRM2 not resolved"]},{"year":2018,"claim":"Discovery that TIAR accumulates in nuclear G2/M transition granules that sequester CDK1, thereby restraining mitotic entry under replication stress, revealed a cell-cycle checkpoint function distinct from its canonical mRNA regulatory roles.","evidence":"Immunofluorescence time-course, TIAR siRNA with genetic epistasis (Cdc25B co-depletion, CDK1 inhibition), CDK1 activity assays","pmids":["30538118"],"confidence":"High","gaps":["Whether CDK1 sequestration requires TIAR RNA binding or phase separation not determined","Upstream signal targeting TIAR to GMGs not identified"]},{"year":2019,"claim":"Demonstration that the C. elegans ortholog TIAR-2 undergoes phosphorylation-regulated liquid-liquid phase separation via its prion-like domain to inhibit axon regeneration provided in vivo evidence that TIAR granule formation is a regulated biophysical process with specific biological consequences.","evidence":"In vitro phase separation assays, PrLD deletion/tyrosine mutants, phosphomutants, axon regeneration assays in C. elegans","pmids":["31378567"],"confidence":"High","gaps":["Whether mammalian TIAR PrLD undergoes analogous regulated phase separation not shown","Kinase responsible for TIAR-2 phosphorylation not identified"]},{"year":2022,"claim":"In vivo CLIP-seq in pro-B cells confirmed that TIA1/TIAL1 bind 5′ splice sites genome-wide for exon definition and showed that their loss deregulates DNA damage sensors (Chek2, Rif1), leading to exacerbated DNA damage and cell death, connecting TIAR's splicing function to genomic integrity.","evidence":"Conditional double knockout in pro-B cells with CLIP-seq and RNA-seq; DNA damage marker analysis","pmids":["36543128"],"confidence":"High","gaps":["Whether TIAR has splicing-independent roles in DNA damage response not tested","Cell-type specificity of the DNA damage phenotype not explored"]},{"year":2023,"claim":"In vivo PAR-CLIP in mouse liver identified Insig2 and ApoB as direct TIAR targets whose translational regulation controls cholesterol homeostasis, while studies in germinal center B cells showed TIAR controls translational identity including MCL1 pro-survival expression, demonstrating tissue-specific translational programs governed by TIAR.","evidence":"viP-CLIP in liver with Tial1 mutant mice and cholesterol phenotyping; conditional B-cell KO with polysome profiling","pmids":["37296170","37474714"],"confidence":"High","gaps":["Full tissue-specific target repertoire remains to be catalogued","How TIAR selects different target sets in different tissues not mechanistically resolved"]},{"year":2025,"claim":"Identification of an RNA-binding-independent interaction between TIAR and SAV1 that disrupts the MST1-SAV1 complex to suppress Hippo signaling expanded TIAR's functional repertoire beyond nucleic acid regulation, and characterization of the TIAR 5′ UTR feature conferring resistance to SARS-CoV-2 Nsp1-mediated translational shutoff revealed a mechanism for TIAR autoprotection during viral infection.","evidence":"Co-IP with RNA-binding-deficient mutants and YAP activity reporters; systematic 5′ UTR mutagenesis in reporter shutoff assays","pmids":["42032365","41407513"],"confidence":"Medium","gaps":["Whether Hippo pathway regulation occurs in vivo in tissues not shown","Whether Nsp1 resistance confers a selective advantage during SARS-CoV-2 infection in physiological context not tested","Single-lab findings for both discoveries"]},{"year":null,"claim":"Major open questions include: the structural basis of TIAR phase separation and granule nucleation in mammalian cells; how upstream signaling pathways (kinases, PTMs) coordinate TIAR's partitioning among splicing, translational repression, stress granule, and Hippo pathway functions; the physiological role of TIAR's high-affinity ssDNA binding; and the tissue-specific logic by which TIAR selects different mRNA target repertoires.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length TIAR or its phase-separated state","Kinase/phosphatase network controlling TIAR localization and function largely unmapped","In vivo relevance of ssDNA binding untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,6,7,8,9,14,16,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[15,16,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,8,9,24,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,11,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3,7,9,24,35]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,10,12,13,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,9,24,27,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,9,25,35]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[32]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[27]}],"complexes":["stress granules","G2/M transition granules"],"partners":["TIA1","HUR","AUF1","FASTK","SAV1","CDK1","HMGB1","HNRNPU"],"other_free_text":[]},"mechanistic_narrative":"TIAL1 (TIAR) is a multi-functional RNA-binding protein containing three RNA recognition motifs (RRMs) that operates as a central post-transcriptional regulator of mRNA splicing, translation, and stress-responsive mRNA triage. RRM2 is the primary high-affinity binding domain for U-rich and C-rich RNA as well as T-rich ssDNA, while RRM1 enhances affinity cooperatively and RRM3 mediates nuclear export; TIAR continuously shuttles between nucleus and cytoplasm via Ran-GTP-dependent import through RRM2 and CRM1-independent export through RRM3 [PMID:8576255, PMID:16278295, PMID:23603827]. TIAR promotes inclusion of alternative exons flanked by U-rich intronic sequences downstream of weak 5′ splice sites genome-wide—including autoregulatory splicing of its own pre-mRNA—and controls expression of DNA damage sensors in pro-B cells [PMID:11514562, PMID:18456862, PMID:36543128]; it represses translation of diverse mRNAs (5′TOP mRNAs, MYC, BRCA1, HIF-1α, translation factors, Insig2/ApoB) by binding 3′-UTR AU-rich or C-rich elements, and assembles into cytoplasmic stress granules downstream of eIF2α phosphorylation to sequester untranslated mRNAs during stress [PMID:10613902, PMID:16537914, PMID:17486099, PMID:21979918, PMID:37296170]. Beyond RNA-dependent functions, TIAR sequesters CDK1 in nuclear G2/M transition granules to restrain mitotic entry, facilitates flavivirus genome amplification by binding minus-strand RNA, and suppresses Hippo signaling through an RNA-binding-independent interaction with SAV1 [PMID:30538118, PMID:18768985, PMID:42032365]."},"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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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":"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":"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":"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":"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":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":"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":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":"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":"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":0,"is_preprint":false},{"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_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_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},{"pmid":null,"id":"bio_10.1101_2024.06.07.597743","title":"Disruption of G3BP1 Granules Promotes Mammalian CNS and PNS Axon Regeneration","date":"2024-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.07.597743","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33898,"output_tokens":8632,"usd":0.115587},"stage2":{"model":"claude-opus-4-6","input_tokens":12516,"output_tokens":4511,"usd":0.263033},"total_usd":0.37862,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Assembly of TIA-1/TIAR-positive stress granules (SGs) is initiated downstream of eIF-2α phosphorylation; a phosphomimetic eIF-2α mutant (S51D) induces SG assembly, a non-phosphorylatable mutant (S51A) prevents it, and a TIAR mutant lacking RNA-binding domains acts as a transdominant inhibitor of SG formation, placing TIAR downstream of eIF-2α in the pathway that sequesters untranslated mRNAs.\",\n      \"method\": \"Phosphomimetic/non-phosphorylatable eIF-2α mutants, transdominant-negative TIAR mutant overexpression, fluorescence microscopy of SG assembly\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic constructs in a single study; foundational paper replicated broadly\",\n      \"pmids\": [\"10613902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RRM2 of both TIA-1 and TIAR is the domain responsible for high-affinity, specific binding to uridylate-rich RNA sequences; RRM1 does not bind cellular RNA in affinity-precipitation assays, while RRM3 binds a broad population of cellular RNAs; affinity increases when RRM2 is expressed together with RRM1 and RRM3.\",\n      \"method\": \"In vitro SELEX, filter-binding assays with individual recombinant RRM domains, affinity precipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays with systematic domain-deletion mutants and Kd measurements\",\n      \"pmids\": [\"8576255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TIAR is concentrated in the nucleus of hematopoietic and non-hematopoietic cells and translocates from the nucleus to the cytoplasm within 30 min of Fas ligation, preceding the onset of DNA fragmentation during Fas-mediated apoptosis; this redistribution is not observed during mitogenic activation.\",\n      \"method\": \"Immunofluorescence microscopy, subcellular fractionation, Fas ligation time-course\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional context (apoptosis timing), replicated in subsequent studies\",\n      \"pmids\": [\"7533298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TIAR binds directly to the AU-rich element (ARE) of TNF-α mRNA (requiring clustered AUUUA pentamers) in the cytoplasm of macrophages, implicating it in translational repression of TNF-α.\",\n      \"method\": \"RNA-protein complex identification by competition gel mobility shift and UV cross-linking, cytoplasmic localization by fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct identification of TIAR in complex with ARE; corroborated by subsequent studies on TNF translation\",\n      \"pmids\": [\"9890998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TIAR is essential for primordial germ cell (PGC) survival and development; TIAR-knockout mice show severely reduced PGC numbers by E11.5 and complete absence by E13.5, and TIAR-deficient ES cells fail to proliferate without exogenous LIF, consistent with a role for TIAR in regulating a survival/proliferation factor.\",\n      \"method\": \"Knockout mouse (gene targeting), embryo staging, methylcellulose ES cell proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific developmental phenotype and cellular assay\",\n      \"pmids\": [\"9482885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIAR (like TIA-1) activates splicing of alternative exons with weak 5' splice sites that are followed by U-rich intronic sequences on the TIA-1 and TIAR pre-mRNAs themselves, demonstrating autoregulatory splicing; in vitro splicing assays showed direct activation requires a downstream U-rich stretch of ≥10 residues.\",\n      \"method\": \"Overexpression in cells, in vitro splicing assays, deletion of U-rich stretches, cryptic splice-site analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro splicing reconstitution plus in vivo overexpression with U-rich element mutagenesis\",\n      \"pmids\": [\"11514562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIAR (p42) was purified by RNA affinity chromatography and identified by peptide sequencing as a specific binding partner of the West Nile virus 3'-terminal minus-strand stem-loop (WNV 3'(-)SL) RNA; binding maps to RRM2 with Kd ~1.5×10⁻⁸ M (10-fold tighter than TIA-1 RRM2); WNV growth is less efficient in TIAR-knockout cells and is partially rescued by TIAR reconstitution.\",\n      \"method\": \"RNA affinity column purification, peptide sequencing, competition gel-shift assays with recombinant proteins, TIAR knockout cell lines, viral reconstitution\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — protein purification and direct Kd measurement; functional confirmation by KO and rescue\",\n      \"pmids\": [\"12414941\"],\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, potently suppressing their translation particularly in response to UVC irradiation; silencing TIAR significantly relieves UVC-induced global translational arrest.\",\n      \"method\": \"RNP immunoprecipitation, polysome profiling, TIAR siRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP combined with knockdown and functional translational readout\",\n      \"pmids\": [\"16537914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AUF1 and TIAR competitively bind the ARE of MYC mRNA to regulate its translation: MYC translation and cell proliferation are proportional to AUF1 abundance and inversely proportional to TIAR abundance; altering one protein's mRNA association reciprocally affects the other's; genetic experiments place both in a MYC-dependent proliferation pathway.\",\n      \"method\": \"ARE-binding competition assays, polysome profiling, siRNA knockdown, genetic epistasis (MYC-dependent pathway)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic epistasis and competitive binding\",\n      \"pmids\": [\"17486099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Upon amino acid starvation, TIAR assembles onto the 5' end of 5'TOP mRNAs and arrests their translation at the initiation step, causing polysome release and accumulation in stress granules; this requires GCN2 kinase activation and mTOR inactivation.\",\n      \"method\": \"Polysome profiling, RIP, siRNA knockdown, stress granule imaging, pharmacological inhibition of GCN2 and mTOR\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — polysome profiling plus pathway-level genetic dissection with multiple orthogonal approaches\",\n      \"pmids\": [\"21979918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Simultaneous knockdown of TIA1 and TIAL1 causes increased skipping of 88% of alternatively spliced exons flanked by U-rich intronic motifs downstream of 5' splice sites, but does not affect exons lacking such motifs, demonstrating a genome-wide role for TIAL1 in promoting exon inclusion via U-rich intronic elements.\",\n      \"method\": \"siRNA knockdown of TIA1/TIAL1, splicing-sensitive microarrays, RT-PCR validation, U-rich motif enrichment analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale knockdown with RT-PCR validation; orthogonal bioinformatics confirms motif specificity\",\n      \"pmids\": [\"18456862\"],\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 drive nuclear accumulation, while RRM3 mediates nuclear export; nuclear import is Ran-GTP-dependent, whereas export is Ran-GTP- and CRM1-independent; both RRMs function through their RNA-binding capacity.\",\n      \"method\": \"GFP-tagged deletion/point mutants, Ran-GTP depletion, CRM1 inhibition (leptomycin B), live-cell imaging, FRAP-like shuttling assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic domain mutagenesis with RNP-motif point mutants and multiple pharmacological controls\",\n      \"pmids\": [\"16278295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fas-activated serine/threonine kinase (FAST K) phosphorylates TIA-1/TIAR and thereby enhances Fas exon 6 inclusion (pro-apoptotic isoform); depletion of FAST K causes exon 6 skipping, overexpression promotes inclusion, and this effect requires both TIA-1/TIAR and a U-rich intronic enhancer downstream of exon 6; in vitro, FAST K phosphorylation of TIA-1 enhances U1 snRNP recruitment without increasing pre-mRNA binding.\",\n      \"method\": \"FAST K depletion/overexpression, TIA-1/TIAR siRNA, minigene splicing reporters with U-rich enhancer mutations, in vitro phosphorylation and U1 snRNP recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation assay combined with in vivo epistasis and mutational analysis\",\n      \"pmids\": [\"17135269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIAR binds a U-tract sequence downstream of a pseudo 5' splice site in the calcitonin/CGRP intron enhancer and promotes inclusion of the upstream alternative 3'-terminal exon; this binding depends on U1 and U6 snRNA interactions with the pseudo 5' splice site, and TIAR binding in turn promotes U6 snRNA binding, revealing a synergistic relationship.\",\n      \"method\": \"RNA affinity pull-down, EMSA, overexpression of dominant-negative TIAR, in vivo splicing reporters, snRNA binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and functional assays with dominant-negative approach\",\n      \"pmids\": [\"12917321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIAR associates with subsets of mRNAs bearing a cytosine-rich (~28-32 nt) stem-loop motif in addition to U-rich sequences; in vitro SPR confirmed TIAR (RRM1-2 and RRM1-3) binding to this C-rich motif; insertion of the motif into a reporter strongly suppressed translation; after UVC stress, target mRNAs dissociate from TIAR and encoded proteins increase in a TIAR-dependent manner.\",\n      \"method\": \"RNP immunoprecipitation + microarray, surface plasmon resonance, reporter translational assays, UVC stress dissociation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding with SPR plus in vivo reporter validation and stress-response dissociation\",\n      \"pmids\": [\"17682065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIAR binds single-stranded, thymidine/uridine-rich DNA with ~6-fold higher affinity than RNA (Kd ~1.6×10⁻⁹ M vs 9.4×10⁻⁹ M for RNA); the high-affinity DNA-binding site maps to RRM2 (overlapping the RNA-binding site); RRM1 alone also binds DNA; active transcription through the binding site can displace TIAR from ssDNA.\",\n      \"method\": \"UV cross-linking, EMSA, TIAR domain truncations, filter-binding affinity measurements\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays with Kd determination and systematic domain mapping\",\n      \"pmids\": [\"16091628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIAR binds both U-rich and AU-rich RNA with nanomolar affinity (higher affinity for U-rich RNA due to faster association); TIAR can also bind deoxy-oligonucleotides with nanomolar affinity whereas HuR affinity for DNA is micromolar; SAXS of TIAR RRM1-2 in complex with RNA shows a flexible, elongated shape distinct from the compact structure of Hu proteins, indicating a different binding mode.\",\n      \"method\": \"Surface plasmon resonance (SPR), SAXS, comparative binding studies with U-rich RNA and DNA\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SPR quantification plus structural SAXS analysis with functional comparison\",\n      \"pmids\": [\"21233170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RRM2 together with its C-terminal six-amino-acid linker extension is the major high-affinity (nM) binding domain for both U-rich RNA and T-rich DNA; RRM1 alone preferentially binds DNA over RNA; NMR spectroscopy identified the specific residues in RRM2+extension involved in RNA contact.\",\n      \"method\": \"SPR, NMR spectroscopy, domain-specific binding assays\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural validation combined with quantitative SPR binding\",\n      \"pmids\": [\"23603827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HuR, TIA-1, TIAR, and hnRNP U form a multimeric protein complex on the first 60 nucleotides of the COX-2 mRNA 3'-UTR (containing AUUUA repeats); this complex represses expression, and IL-1β stimulation increases cytosolic HuR binding and COX-2 mRNA levels.\",\n      \"method\": \"EMSA, immunoprecipitation of complex members, reporter gene assay with 60-nt 3'-UTR insert\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab EMSA/IP; functional reporter confirms regulatory role\",\n      \"pmids\": [\"12855701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIAR binds the AU-rich sequence (5'-UUUUAAAUUUU) in Sendai virus trailer RNA; sequestration of TIAR by this viral RNA has an anti-apoptotic effect; transgenic overexpression of TIAR during SeV infection promotes apoptosis and reverses the anti-apoptotic effect of trailer RNA expression.\",\n      \"method\": \"In vitro binding assays, transgenic TIAR overexpression, apoptosis assays in mixed infections\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding plus functional overexpression with apoptosis readout\",\n      \"pmids\": [\"12356730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In West Nile virus- and dengue virus-infected cells, TIAR and TIA-1 co-localize with viral replication complex components (dsRNA, NS3) in perinuclear regions; TIAR relocates coincident with peak RNA synthesis, and this interaction suppresses stress granule formation and progressively reduces processing body numbers.\",\n      \"method\": \"Immunofluorescence co-localization, kinetic analysis of TIAR redistribution vs. RNA synthesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-localization imaging without biochemical co-IP; functional SG suppression confirmed\",\n      \"pmids\": [\"17502609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TIA-1/TIAR binding sites on the WNV 3'(-)SL RNA were mapped to short AU sequences (UAAUU) in two internal stem-loop loops; mutations abolishing TIAR/TIA-1 binding in infectious clones proportionally reduce viral genomic RNA amplification (not translation), with lethal mutations reverting in vivo, indicating these proteins facilitate asymmetric genome amplification from the minus-strand template.\",\n      \"method\": \"Infectious clone mutagenesis, in vitro binding assays, plaque assays, intracellular RNA quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis in infectious clone correlated with quantitative binding and replication data\",\n      \"pmids\": [\"18768985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"An alternatively spliced form of TIAR (containing a 17-amino-acid insert) is expressed in human but not rat cells and is required for species-dependent translational repression of HMMP13 mRNA; transient expression of the insert reverses silencing in human cells, and co-transfection of this isoform suppresses HMMP13 protein expression in Rat2 cells.\",\n      \"method\": \"Reporter assays, transient expression of TIAR isoform and insert peptide, species comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific functional assay with cross-species rescue\",\n      \"pmids\": [\"12426321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIAR accumulates in nuclear foci (G2/M transition granules, GMGs) during late G2/prophase under replication stress; GMGs contain CDK1, and TIAR retains CDK1 in these granules to attenuate its activity; depletion of TIAR accelerates mitotic entry and causes chromosomal instability that is rescued by co-depletion of Cdc25B or CDK1 inhibition.\",\n      \"method\": \"Immunofluorescence time-course, TIAR siRNA, genetic epistasis with Cdc25B/CDK1, CDK1 activity assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific mitotic phenotype, genetic epistasis with CDK1/Cdc25B, and CDK1 retention mechanism\",\n      \"pmids\": [\"30538118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In BCR-ABL1-positive CML cells, ER stress promotes cytosolic localization of TIAR, its binding to BRCA1 mRNA 3'-UTR, and formation of a TIAR-HuR complex; TIAR negatively regulates BRCA1 mRNA translation (demonstrated by polysome profiling and luciferase-BRCA1 3'-UTR reporter), and TIAR silencing strongly elevates BRCA1 protein levels.\",\n      \"method\": \"Polysome profiling, luciferase-3'UTR reporter, RNA immunoprecipitation, TIAR siRNA knockdown, subcellular fractionation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods showing TIAR-dependent translational repression\",\n      \"pmids\": [\"25483082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Under acute/severe hypoxia, TIAR and TIA-1 co-aggregate into stress granules (co-staining with eIF3η); HIF-1α expression is blocked in cells displaying TIAR/TIA-1 granules; TIAR/TIA-1 silencing upregulates HIF-1α; ARE in HIF-1α 3'-UTR drives TIAR-dependent translational suppression in reporter assays.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, HIF-1α reporter with 3'-UTR ARE, western blot\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter and knockdown confirm mechanism but single laboratory\",\n      \"pmids\": [\"20980400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LncRNA MT1JP interacts with TIAR (RNA-binding protein) to enhance translation of p53 mRNA; MT1JP down-regulation reduces p53 protein without affecting mRNA, and this effect is mediated through TIAR.\",\n      \"method\": \"RNA pull-down, RIP, polysome analysis, siRNA knockdown, luciferase reporter\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with multiple assays; indirect evidence for TIAR as effector\",\n      \"pmids\": [\"26909858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In vivo PAR-CLIP (viP-CLIP) in mouse liver identified Insig2 and ApoB mRNAs as prominent TIAL1 targets; TIAL1 influences their translation in hepatocytes; Tial1 mutant mice exhibit altered cholesterol synthesis, APOB secretion, and plasma cholesterol levels, placing TIAL1 in negative feedback regulation of cholesterol biosynthesis.\",\n      \"method\": \"In vivo PAR-CLIP in liver tissue, translation assays in hepatocytes, Tial1 mutant mice with cholesterol phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo CLIP combined with KO mouse metabolic phenotype and hepatocyte translational assays\",\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 differentially regulates translation: TIAR increases Pol translation while decreasing Cp translation from the same pgRNA; HBV replication or Cp expression induces TIAR nuclear-to-cytoplasmic redistribution, creating a feedback loop that balances Cp and Pol levels.\",\n      \"method\": \"Ribo-seq, PRM mass spectrometry, RIP, RNA pulldown, Cp/Pol expression measurement, TIAR subcellular redistribution imaging\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Ribo-seq and proteomics quantify translational shift; direct binding to 5'ε confirmed\",\n      \"pmids\": [\"37699883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIA1 and TIAL1 act as global splicing regulators in pro-B cells, binding 5' splice sites for exon definition to control expression of DNA damage sensors including Chek2 and Rif1; double knockout leads to exacerbated DNA damage, altered p53, and increased cell death.\",\n      \"method\": \"Conditional knockout, RNA-seq, CLIP-seq (binding at 5' splice sites), western blot for DNA damage markers\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with genome-wide splicing readout and mechanistic binding data\",\n      \"pmids\": [\"36543128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIA1 and TIAL1 are required for germinal center B cell positive selection and differentiation; they control the translational identity of dark- and light-zone GC B cells and enable timely expression of the pro-survival molecule MCL1.\",\n      \"method\": \"Conditional knockout in B cells, germinal center assays, polysome profiling for MCL1, flow cytometry\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with specific GC phenotype and mechanistic translational readout\",\n      \"pmids\": [\"37474714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans TIAR-2 undergoes liquid-liquid phase separation via its C-terminal prion-like domain (PrLD) and forms liquid-like granules in vivo that inhibit axon regeneration cell-autonomously; axon injury transiently increases granule number; non-phosphorylatable TIAR-2 variants fail to form granules and cannot inhibit regeneration; tyrosine residues in the PrLD are important for granule formation.\",\n      \"method\": \"In vitro phase separation assay, live imaging of granule dynamics (liquid-like properties), PrLD deletion/tyrosine mutants, phosphorylation mutants, axon regeneration assays in C. elegans\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of phase separation plus in vivo mutagenesis with specific regeneration phenotype\",\n      \"pmids\": [\"31378567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TIAL1 directly interacts with the Hippo pathway component SAV1, disrupting the MST1-SAV1 interaction and thereby suppressing Hippo signaling to activate YAP; this function is independent of TIAL1's RNA-binding activity; extracellular stimuli (energy surplus, EGF) upregulate TIAL1 expression to modulate this pathway.\",\n      \"method\": \"Co-immunoprecipitation, RNA-binding-deficient TIAL1 mutants, MST1-SAV1 interaction assays, YAP activity reporters\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and RNA-binding-independent mutants; single-lab study\",\n      \"pmids\": [\"42032365\"],\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 NMD, revealing a TIA-1-mediated autoregulatory loop that controls TIAR expression at the splicing level.\",\n      \"method\": \"Gene targeting in DT40 cells, RT-PCR, cycloheximide treatment (NMD assay), TIA-1 expression rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in KO cells with NMD validation\",\n      \"pmids\": [\"12533540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The first 23 nucleotides of the TIAR 5' UTR are necessary and sufficient to confer resistance to SARS-CoV-2 Nsp1-mediated host translational shutoff; the absence of guanosines within positions 10-18 from the 5' end is the defining sequence feature shared between TIAR 5' UTR and the viral leader that confers Nsp1 resistance.\",\n      \"method\": \"Reporter shutoff assays with TIAR 5' UTR deletion/substitution mutants, sequence comparison with SARS-CoV-2 leader\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis in reporter assay; single lab\",\n      \"pmids\": [\"41407513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxia-induced lactylation of HMGB1 at K177 drives its nuclear export in a complex with TIAR, promoting stress granule formation in the cytosol; K177R mutation blocks this HMGB1-TIAR complex export and subsequent SG assembly; other stressors (arsenite, heat shock) trigger TIAR nuclear export and SG assembly independently of HMGB1.\",\n      \"method\": \"Mass spectrometry for lactylation sites, K→R mutagenesis, co-IP of HMGB1-TIAR complex, immunofluorescence of SG formation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PTM-specific mutagenesis with Co-IP and functional SG readout; single-lab study\",\n      \"pmids\": [\"40788094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHAROH lncRNA sequesters TIAR via a 71-nt hairpin within PHAROH (identified by RNA-antisense pulldown), preventing TIAR from repressing MYC translation; PHAROH knockout decreases MYC protein without affecting mRNA.\",\n      \"method\": \"RNA-antisense pulldown, MYC protein/mRNA measurement in PHAROH KO cells, rescue by PHAROH re-expression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding identified by pulldown; MYC translational effect validated in KO\",\n      \"pmids\": [\"34002693\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIAL1 (TIAR) is an RNA-binding protein with three RRM domains (RRM2 being the primary high-affinity binding domain for U-rich and C-rich RNA/ssDNA sequences) that operates at multiple post-transcriptional levels: it represses translation of specific mRNAs (including 5'TOP mRNAs, translation factors, MYC, BRCA1, HIF-1α) by binding their 3'-UTRs, promotes inclusion of alternative exons with weak 5' splice sites flanked by U-rich intronic sequences, assembles into cytoplasmic stress granules downstream of eIF-2α phosphorylation to sequester untranslated mRNAs during stress, undergoes regulated nuclear-cytoplasmic shuttling (nuclear import via Ran-GTP/RRM2; export via RRM3), facilitates flavivirus genome RNA amplification by binding viral minus-strand RNA, restrains CDK1 activity during the G2/M checkpoint by sequestering it in nuclear G2/M transition granules, and can act through an RNA-binding-independent mechanism by interacting with SAV1 to suppress Hippo signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TIAL1 (TIAR) is a multi-functional RNA-binding protein containing three RNA recognition motifs (RRMs) that operates as a central post-transcriptional regulator of mRNA splicing, translation, and stress-responsive mRNA triage. RRM2 is the primary high-affinity binding domain for U-rich and C-rich RNA as well as T-rich ssDNA, while RRM1 enhances affinity cooperatively and RRM3 mediates nuclear export; TIAR continuously shuttles between nucleus and cytoplasm via Ran-GTP-dependent import through RRM2 and CRM1-independent export through RRM3 [PMID:8576255, PMID:16278295, PMID:23603827]. TIAR promotes inclusion of alternative exons flanked by U-rich intronic sequences downstream of weak 5′ splice sites genome-wide—including autoregulatory splicing of its own pre-mRNA—and controls expression of DNA damage sensors in pro-B cells [PMID:11514562, PMID:18456862, PMID:36543128]; it represses translation of diverse mRNAs (5′TOP mRNAs, MYC, BRCA1, HIF-1α, translation factors, Insig2/ApoB) by binding 3′-UTR AU-rich or C-rich elements, and assembles into cytoplasmic stress granules downstream of eIF2α phosphorylation to sequester untranslated mRNAs during stress [PMID:10613902, PMID:16537914, PMID:17486099, PMID:21979918, PMID:37296170]. Beyond RNA-dependent functions, TIAR sequesters CDK1 in nuclear G2/M transition granules to restrain mitotic entry, facilitates flavivirus genome amplification by binding minus-strand RNA, and suppresses Hippo signaling through an RNA-binding-independent interaction with SAV1 [PMID:30538118, PMID:18768985, PMID:42032365].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that TIAR is a predominantly nuclear protein that undergoes regulated nuclear-to-cytoplasmic redistribution during apoptosis resolved where and when TIAR acts, linking its subcellular dynamics to cell-death signaling.\",\n      \"evidence\": \"Immunofluorescence and subcellular fractionation during Fas-ligation time-course in hematopoietic cells\",\n      \"pmids\": [\"7533298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear export during apoptosis not defined\", \"Whether redistribution is required for apoptosis execution not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping high-affinity U-rich RNA binding to RRM2 (with cooperative contributions from RRM1 and RRM3) defined the molecular basis for TIAR target recognition, enabling all subsequent studies of its RNA-binding specificity.\",\n      \"evidence\": \"SELEX, filter-binding, and affinity precipitation with individual recombinant RRM domains\",\n      \"pmids\": [\"8576255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RRM2 selectivity not yet resolved\", \"In vivo target spectrum not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that TIAR-knockout mice lose primordial germ cells and that TIAR-deficient ES cells require exogenous LIF for proliferation established TIAR as essential for cell survival and germ cell development.\",\n      \"evidence\": \"Gene-targeted knockout mice with embryonic staging; ES cell proliferation assay in methylcellulose\",\n      \"pmids\": [\"9482885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mRNA targets mediating PGC survival not identified\", \"Redundancy with TIA-1 in vivo not fully dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placing TIAR downstream of eIF2α phosphorylation in stress granule assembly provided the first mechanistic framework for how cells sequester untranslated mRNAs during stress, and showing that TIAR also binds TNF-α ARE linked it to cytokine translational control.\",\n      \"evidence\": \"Phosphomimetic/non-phosphorylatable eIF2α mutants with SG imaging; UV cross-linking and gel-shift with TNF-α ARE\",\n      \"pmids\": [\"10613902\", \"9890998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIAR nucleates SG condensation mechanistically was unknown\", \"Relative contributions of TIA-1 vs TIAR to SG nucleation not separated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that TIAR activates inclusion of alternative exons with weak 5′ splice sites by binding downstream U-rich intronic sequences—including autoregulatory exons in its own pre-mRNA—established TIAR as a sequence-specific splicing activator.\",\n      \"evidence\": \"In vitro splicing reconstitution with U-rich element deletions; in vivo overexpression with minigene reporters\",\n      \"pmids\": [\"11514562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIAR promotes U1 snRNP recruitment mechanistically was unclear\", \"Genome-wide scope of splicing regulation not yet measured\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of TIAR as a high-affinity binding partner of the WNV minus-strand 3′ stem-loop, with reduced viral growth in TIAR-KO cells, revealed an unexpected role for a host RNA-binding protein in flavivirus genome amplification.\",\n      \"evidence\": \"RNA affinity purification, peptide sequencing, Kd measurement, TIAR-KO cell viral growth and rescue\",\n      \"pmids\": [\"12414941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise mechanism by which TIAR facilitates minus-to-plus strand synthesis not defined\", \"Applicability to other flaviviruses not yet tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining that TIAR continuously shuttles between nucleus and cytoplasm—with RRM2 driving Ran-GTP-dependent nuclear import and RRM3 mediating CRM1-independent export—explained how TIAR can function in both nuclear splicing and cytoplasmic translational control, and revealing high-affinity ssDNA binding expanded the repertoire of potential TIAR substrates.\",\n      \"evidence\": \"GFP-domain mutants with Ran depletion and leptomycin B treatment; UV cross-linking and EMSA with ssDNA Kd measurements\",\n      \"pmids\": [\"16278295\", \"16091628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of DNA binding in vivo not demonstrated\", \"Export receptor/adaptor identity unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that TIAR represses translation of mRNAs encoding translation factors and c-Myc via 3′-UTR binding, and that FASTK phosphorylation of TIA-1/TIAR enhances U1 snRNP recruitment for Fas exon 6 splicing, revealed dual regulatory outputs (translational repression and splicing activation) modulated by upstream kinase signaling.\",\n      \"evidence\": \"RNP-IP with polysome profiling and siRNA knockdown; FASTK phosphorylation assays with minigene splicing reporters\",\n      \"pmids\": [\"16537914\", \"17135269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full kinase network regulating TIAR not mapped\", \"Whether FASTK also regulates TIAR's translational function not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that TIAR binds a C-rich stem-loop motif in addition to U-rich sequences, and that AUF1 and TIAR competitively regulate MYC mRNA translation, broadened the RNA target code and revealed combinatorial control of specific transcripts.\",\n      \"evidence\": \"RNP-IP/microarray with SPR validation for C-rich motif; competitive ARE-binding and polysome profiling for MYC regulation\",\n      \"pmids\": [\"17682065\", \"17486099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for C-rich motif recognition not determined\", \"How the AUF1-TIAR balance is regulated upstream not known\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genome-wide splicing analysis confirmed that TIA1/TIAL1 control ~88% of alternative exons flanked by downstream U-rich motifs, and infectious-clone mutagenesis mapped the precise TIAR-binding sites on WNV minus-strand RNA required for viral genome amplification.\",\n      \"evidence\": \"Splicing-sensitive microarray after TIA1/TIAL1 knockdown; WNV infectious clone mutagenesis with binding and replication assays\",\n      \"pmids\": [\"18456862\", \"18768985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIAR binding promotes asymmetric replication mechanistically not resolved\", \"Redundancy between TIA-1 and TIAR in splicing regulation not fully dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that TIAR assembles onto 5′TOP mRNAs during amino acid starvation downstream of GCN2 activation and mTOR inactivation placed TIAR in a nutrient-sensing translational repression pathway, and biophysical characterization revealed that TIAR RRM1-2 adopts an elongated conformation distinct from HuR, explaining differential RNA/DNA binding modes.\",\n      \"evidence\": \"Polysome profiling with RIP under amino acid starvation, GCN2/mTOR inhibition; SPR and SAXS structural analysis\",\n      \"pmids\": [\"21979918\", \"21233170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIAR recognizes 5′TOP sequences specifically vs general U-rich elements not clarified\", \"Whether elongated conformation is altered by post-translational modifications unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"NMR mapping of the RNA-contacting residues in RRM2 plus its C-terminal six-amino-acid linker provided the first atomic-level view of TIAR's primary RNA-binding surface.\",\n      \"evidence\": \"NMR spectroscopy combined with SPR binding of domain-specific constructs\",\n      \"pmids\": [\"23603827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution co-crystal structure of RRM2-RNA complex\", \"How RRM1 and RRM3 cooperate structurally with RRM2 not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that TIAR accumulates in nuclear G2/M transition granules that sequester CDK1, thereby restraining mitotic entry under replication stress, revealed a cell-cycle checkpoint function distinct from its canonical mRNA regulatory roles.\",\n      \"evidence\": \"Immunofluorescence time-course, TIAR siRNA with genetic epistasis (Cdc25B co-depletion, CDK1 inhibition), CDK1 activity assays\",\n      \"pmids\": [\"30538118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK1 sequestration requires TIAR RNA binding or phase separation not determined\", \"Upstream signal targeting TIAR to GMGs not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that the C. elegans ortholog TIAR-2 undergoes phosphorylation-regulated liquid-liquid phase separation via its prion-like domain to inhibit axon regeneration provided in vivo evidence that TIAR granule formation is a regulated biophysical process with specific biological consequences.\",\n      \"evidence\": \"In vitro phase separation assays, PrLD deletion/tyrosine mutants, phosphomutants, axon regeneration assays in C. elegans\",\n      \"pmids\": [\"31378567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian TIAR PrLD undergoes analogous regulated phase separation not shown\", \"Kinase responsible for TIAR-2 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vivo CLIP-seq in pro-B cells confirmed that TIA1/TIAL1 bind 5′ splice sites genome-wide for exon definition and showed that their loss deregulates DNA damage sensors (Chek2, Rif1), leading to exacerbated DNA damage and cell death, connecting TIAR's splicing function to genomic integrity.\",\n      \"evidence\": \"Conditional double knockout in pro-B cells with CLIP-seq and RNA-seq; DNA damage marker analysis\",\n      \"pmids\": [\"36543128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TIAR has splicing-independent roles in DNA damage response not tested\", \"Cell-type specificity of the DNA damage phenotype not explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo PAR-CLIP in mouse liver identified Insig2 and ApoB as direct TIAR targets whose translational regulation controls cholesterol homeostasis, while studies in germinal center B cells showed TIAR controls translational identity including MCL1 pro-survival expression, demonstrating tissue-specific translational programs governed by TIAR.\",\n      \"evidence\": \"viP-CLIP in liver with Tial1 mutant mice and cholesterol phenotyping; conditional B-cell KO with polysome profiling\",\n      \"pmids\": [\"37296170\", \"37474714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full tissue-specific target repertoire remains to be catalogued\", \"How TIAR selects different target sets in different tissues not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of an RNA-binding-independent interaction between TIAR and SAV1 that disrupts the MST1-SAV1 complex to suppress Hippo signaling expanded TIAR's functional repertoire beyond nucleic acid regulation, and characterization of the TIAR 5′ UTR feature conferring resistance to SARS-CoV-2 Nsp1-mediated translational shutoff revealed a mechanism for TIAR autoprotection during viral infection.\",\n      \"evidence\": \"Co-IP with RNA-binding-deficient mutants and YAP activity reporters; systematic 5′ UTR mutagenesis in reporter shutoff assays\",\n      \"pmids\": [\"42032365\", \"41407513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Hippo pathway regulation occurs in vivo in tissues not shown\", \"Whether Nsp1 resistance confers a selective advantage during SARS-CoV-2 infection in physiological context not tested\", \"Single-lab findings for both discoveries\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the structural basis of TIAR phase separation and granule nucleation in mammalian cells; how upstream signaling pathways (kinases, PTMs) coordinate TIAR's partitioning among splicing, translational repression, stress granule, and Hippo pathway functions; the physiological role of TIAR's high-affinity ssDNA binding; and the tissue-specific logic by which TIAR selects different mRNA target repertoires.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length TIAR or its phase-separated state\", \"Kinase/phosphatase network controlling TIAR localization and function largely unmapped\", \"In vivo relevance of ssDNA binding untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 6, 7, 8, 9, 14, 16, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [15, 16, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 8, 9, 24, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 11, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3, 7, 9, 24, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 10, 12, 13, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 9, 24, 27, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 9, 25, 35]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [\n      \"stress granules\",\n      \"G2/M transition granules\"\n    ],\n    \"partners\": [\n      \"TIA1\",\n      \"HuR\",\n      \"AUF1\",\n      \"FASTK\",\n      \"SAV1\",\n      \"CDK1\",\n      \"HMGB1\",\n      \"hnRNPU\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}