Affinage

TIAL1

Nucleolysin TIAR · UniProt Q01085

Length
375 aa
Mass
41.6 kDa
Annotated
2026-06-10
65 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIAL1 (TIAR) is a multifunctional RNA-binding protein that couples cellular stress to post-transcriptional control of gene expression, acting as a nucleator of cytoplasmic stress granules, a translational repressor of specific mRNAs, and a sequence-specific regulator of alternative splicing (PMID:10613902, PMID:16537914, PMID:18456862). Its RNA/DNA recognition is built on three RRMs, of which RRM2 plus a short C-terminal linker constitutes the major high-affinity (nanomolar) module for U-rich RNA and T-rich single-stranded DNA, while RRM1 contributes DNA preference and RRM3 binds a broad RNA population and drives nuclear export (PMID:8576255, PMID:16091628, PMID:23603827). The two N-terminal domains adopt a flexible elongated conformation upon RNA binding, distinguishing TIAR's binding mode from related Hu proteins (PMID:21233170). In the cytoplasm, TIAR assembles stress granules downstream of eIF-2alpha phosphorylation and represses translation of ARE- and C-rich-motif-containing target mRNAs including TNF-alpha, MYC, the translation factors eIF4A/eIF4E, 5'TOP mRNAs, HIF-1alpha, and BRCA1, frequently in competition or partnership with HuR and AUF1 (PMID:10613902, PMID:9890998, PMID:21979918, PMID:17486099, PMID:16537914, PMID:17682065, PMID:20980400, PMID:25483082). In the nucleus, TIAR activates inclusion of alternative cassette exons that carry weak 5' splice sites followed by U-rich intronic stretches—a mechanism covering roughly 15% of alternatively spliced exons genome-wide and including autoregulatory cross-control whereby TIA-1 drives an NMD-coupled TIAR splicing event to set TIAR levels (PMID:11514562, PMID:18456862, PMID:12533540). TIAR shuttles continuously between nucleus and cytoplasm, with import requiring RRM2/auxiliary regions in a Ran-GTP-dependent manner and CRM1-independent export via RRM3, and it redistributes to the cytoplasm under apoptotic and stress signals (PMID:7533298, PMID:16278295). Through these activities TIAR is essential for primordial germ cell survival, governs a G2/M checkpoint by sequestering and attenuating CDK1 in nuclear G2/M transition granules under replication stress, and supports germinal-center B-cell survival via MCL1 translation and pro-B-cell DNA-repair splicing programs (PMID:9482885, PMID:30538118, PMID:36543128, PMID:37474714). TIAR is additionally co-opted by viral RNAs to facilitate flavivirus (West Nile, dengue) genome amplification and HBV replication, and it suppresses Hippo signaling through an RNA-binding-independent protein interaction with SAV1 (PMID:12414941, PMID:17502609, PMID:37699883, PMID:42032365, PMID:18768985).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1996 High

    Established which domain confers TIAR's RNA-binding specificity, defining RRM2 as the determinant of U-rich sequence recognition.

    Evidence SELEX from random RNA pools with domain deletion mutants and filter-binding affinity measurement

    PMID:8576255

    Open questions at the time
    • Did not resolve atomic contacts or the role of the C-terminal linker
    • RRM1's apparent inability to bind RNA later contrasted with its DNA binding
  2. 1995 High

    Showed that TIAR localization is stimulus-responsive, redistributing from nucleus to cytoplasm during apoptosis before DNA fragmentation.

    Evidence Immunofluorescence and fractionation during Fas-mediated apoptosis time course

    PMID:7533298

    Open questions at the time
    • Did not define the signal or transport machinery driving redistribution
    • Functional consequence of cytoplasmic TIAR not mechanistically dissected here
  3. 1998 High

    Demonstrated an essential physiological requirement for TIAR in primordial germ cell survival via knockout phenotype.

    Evidence TIAR knockout mouse with embryo histology and ES cell proliferation assay

    PMID:9482885

    Open questions at the time
    • Did not identify the mRNA targets responsible for PGC survival
    • Molecular basis of the ES cell LIF-dependent proliferation defect unresolved
  4. 1999 High

    Placed TIAR/TIA-1 downstream of eIF-2alpha phosphorylation as a nucleator of stress granule assembly and translational arrest.

    Evidence Phosphomimetic/nonphosphorylatable eIF-2alpha mutants and dominant-negative TIA-1, fluorescence microscopy

    PMID:10613902

    Open questions at the time
    • Did not define which RNAs are recruited into granules
    • Mechanism of self-aggregation/granule nucleation not resolved
  5. 1999 Medium

    Connected TIAR to a defined cytokine mRNA target by showing ARE-dependent binding to TNF-alpha mRNA.

    Evidence EMSA and immunoprecipitation in macrophage cytoplasmic fractions

    PMID:9890998

    Open questions at the time
    • Functional translational repression inferred, not directly demonstrated in this study
    • Single lab without reciprocal validation
  6. 2001 High

    Defined TIAR's splicing-activator mechanism: recognition of U-rich intronic stretches downstream of weak 5' splice sites, including autoregulatory exons.

    Evidence In vitro splicing assays and minigene reporters with U-rich deletion mutagenesis

    PMID:11514562

    Open questions at the time
    • Did not establish genome-wide scope at this stage
    • snRNP recruitment mechanism not yet defined
  7. 2002 High

    Revealed that TIAR is hijacked by a viral RNA element, binding the WNV minus-strand 3' stem-loop and supporting replication.

    Evidence RNA affinity purification, Kd measurement, and virus growth in knockout/reconstituted cells

    PMID:12414941

    Open questions at the time
    • Mechanism by which binding promotes replication not yet defined here
    • Distinction between TIAR and TIA-1 roles unresolved
  8. 2003 High

    Established a self-regulatory circuit whereby TIA-1 controls TIAR abundance through splicing-coupled NMD.

    Evidence Conditional gene disruption in DT40 cells with RT-PCR, cycloheximide NMD assay, and rescue

    PMID:12533540

    Open questions at the time
    • Did not map the full set of co-regulated targets
    • Physiological setting of autoregulation in mammalian tissues unaddressed here
  9. 2003 Medium

    Showed mechanistic interplay between TIAR and the spliceosome, with synergistic U6 snRNA recruitment at a pseudo 5' splice site enhancer.

    Evidence UV cross-linking, EMSA, dominant-negative TIAR, and minigene reporters with snRNA interaction analysis

    PMID:12917321

    Open questions at the time
    • No in vitro reconstitution of the synergistic complex
    • Single-lab evidence
  10. 2006 High

    Identified translation factor mRNAs and c-Myc as direct TIAR-repressed targets mediating UVC-induced translational shutdown.

    Evidence RIP, reporters, siRNA rescue, and polysome profiling under UVC stress

    PMID:16537914

    Open questions at the time
    • Did not establish whether repression occurs in stress granules or by direct initiation block
    • Selectivity rules among 3'UTR targets unresolved
  11. 2007 High

    Demonstrated competitive control of MYC mRNA between TIAR and AUF1, linking TIAR abundance inversely to proliferation.

    Evidence RIP, reporters, siRNA/overexpression, and proliferation assays with genetic epistasis

    PMID:17486099

    Open questions at the time
    • Molecular basis of the reciprocal binding competition not structurally defined
    • Generality across other ARE targets not tested
  12. 2007 Medium

    Expanded TIAR's binding repertoire beyond U-rich motifs to a C-rich stem-loop and showed stress-induced dissociation derepresses targets.

    Evidence RIP-chip, SPR binding, and luciferase reporters under UVC stress

    PMID:17682065

    Open questions at the time
    • Signal triggering target release from TIAR under stress not identified
    • Single-lab characterization of C-rich binding mode
  13. 2008 High

    Quantified the genome-wide scope of TIA1/TIAL1-dependent splicing, attributing ~15% of cassette exon regulation to U-rich intronic motifs.

    Evidence Double siRNA knockdown with splicing microarray, RT-PCR validation, and motif analysis

    PMID:18456862

    Open questions at the time
    • Redundancy partitioning between TIA1 and TIAL1 not resolved per-target
    • Tissue-specific splicing programs not addressed
  14. 2011 High

    Defined the 5'TOP mRNA arrest mechanism, showing TIAR assembles on 5' ends to block initiation under amino acid starvation via GCN2/mTOR signaling.

    Evidence RIP, polysome profiling, siRNA, reporters, and stress granule imaging

    PMID:21979918

    Open questions at the time
    • Direct contact between TIAR and 5'TOP elements not structurally mapped
    • Relationship to canonical TOP regulators left open
  15. 2011 High

    Provided structural insight distinguishing TIAR from Hu proteins, with a flexible elongated conformation and unusually strong DNA binding.

    Evidence SPR and SAXS with DNA/RNA variant comparison

    PMID:21233170

    Open questions at the time
    • No high-resolution complex structure
    • Functional importance of the elongated conformation in cells untested
  16. 2013 High

    Pinpointed the minimal high-affinity module as RRM2 plus a six-residue C-terminal linker, identifying residues engaging AU-rich RNA.

    Evidence SPR and NMR with domain truncations

    PMID:23603827

    Open questions at the time
    • Linker's structural role not fully visualized in a complex
    • How RRM1 and RRM3 cooperate with RRM2 in vivo unresolved
  17. 2018 High

    Uncovered a nuclear G2/M checkpoint function in which TIAR sequesters and attenuates CDK1 in transition granules under replication stress.

    Evidence siRNA, immunofluorescence, flow cytometry, CDK1 activity assay, and epistasis with Cdc25B/CDK1 inhibition

    PMID:30538118

    Open questions at the time
    • Whether RNA binding is required for GMG assembly not resolved
    • Composition and biogenesis of GMGs only partially defined
  18. 2022 High

    Established a developmental splicing program in which TIA1/TIAL1 redundantly control DNA-repair gene splicing to protect pro-B cells.

    Evidence Conditional double knockout with iCLIP, RNA-seq, splicing RT-PCR, and DNA damage readouts

    PMID:36543128

    Open questions at the time
    • Individual contributions of Chek2 vs Rif1 mis-splicing to the phenotype not isolated
    • Whether translational targets also contribute unaddressed
  19. 2023 High

    Demonstrated an in vivo metabolic role, with hepatic TIAL1 controlling Insig2/ApoB translation and cholesterol homeostasis.

    Evidence In vivo PAR-CLIP in mouse liver, hepatocyte translation assays, and Tial1 mutant cholesterol/APOB phenotyping

    PMID:37296170

    Open questions at the time
    • Whether translation is enhanced or repressed per target not uniformly resolved
    • Mechanistic link to the cholesterol feedback loop only correlative
  20. 2023 High

    Showed TIAR differentially controls translation of two proteins from one HBV pgRNA template via 5' stem-loop binding to promote replication.

    Evidence RIP/pulldown, Ribo-seq, PRM mass spectrometry, and loss/gain-of-function

    PMID:37699883

    Open questions at the time
    • Mechanism producing opposite effects on Pol vs Cp not resolved
    • Trigger for TIAR nuclear-to-cytoplasm redistribution during infection unclear
  21. 2023 High

    Identified MCL1 mRNA translation as the TIA1/TIAL1-dependent pathway sustaining germinal center B-cell survival and selection.

    Evidence Conditional double knockout mice with GC phenotyping and polysome profiling

    PMID:37474714

    Open questions at the time
    • Whether MCL1 is a direct binding target shown by CLIP not established here
    • Contribution of splicing vs translational control to the phenotype not separated
  22. 2025 Medium

    Revealed an RNA-binding-independent function: TIAL1 binds SAV1 to disrupt MST1-SAV1 and suppress Hippo signaling, activating YAP.

    Evidence Co-IP, RNA-binding-deficient mutants, YAP reporter, and MST1-SAV1 interaction assays in HCC cells

    PMID:42032365

    Open questions at the time
    • Recently published without independent replication
    • Structural basis of the TIAL1-SAV1 interaction undefined
  23. 2025 Medium

    Linked hypoxia metabolism to TIAR trafficking via HMGB1 K177 lactylation driving HMGB1-TIAR co-export and stress granule formation.

    Evidence Mass spectrometry of lactylation sites, K177R mutant, co-IP, and SG imaging

    PMID:40788094

    Open questions at the time
    • Single-lab and recently published
    • How the HMGB1-TIAR complex nucleates SGs mechanistically unresolved
  24. 2025 Medium

    Defined a sequence determinant in the TIAR 5'UTR that confers resistance to SARS-CoV-2 Nsp1 translation shutoff.

    Evidence Reporter shutoff assays with 5'UTR truncation/mutation constructs

    PMID:41407513

    Open questions at the time
    • Does not establish the cellular consequence of TIAR escaping shutoff
    • Mechanism by which guanosine absence confers resistance not biochemically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TIAR's distinct activities—splicing activation, translational repression, granule nucleation, and RNA-binding-independent signaling—are coordinated and switched within a single cell remains unresolved.
  • No integrated model linking domain conformation to functional mode switching
  • Signal-specific rules governing TIAR localization and target selection undefined
  • No high-resolution structure of TIAR bound to a physiological target

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0045182 translation regulator activity 6 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1640170 Cell Cycle 1
Partners
AUF1CDK1HMGB1HNRNP UHURSAV1TIA1
Complex memberships
G2/M transition granules (GMGs)stress granule

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TIAR (and TIA-1) colocalize with poly(A)+ RNA at cytoplasmic stress granules; stress granule assembly is initiated downstream of eIF-2alpha phosphorylation at S51, and a TIA-1 mutant lacking RNA-binding domains acts as a transdominant inhibitor of stress granule formation, placing TIAR/TIA-1 downstream of eIF-2alpha phosphorylation in the stress-induced translational arrest pathway. Fluorescence microscopy, phosphomimetic (S51D) and nonphosphorylatable (S51A) eIF-2alpha mutant transfection, dominant-negative TIA-1 mutant transfection The Journal of cell biology High 10613902
1999 TIAR binds to the AU-rich element (ARE) of TNF-alpha mRNA (complex 1 requiring clustered AUUUA pentamers) in the cytoplasm of macrophages, implicating TIAR in post-transcriptional regulation of TNF-alpha translation. RNA electrophoretic mobility shift assay (EMSA), protein identification by immunoprecipitation, cytoplasmic localization by fractionation The Journal of biological chemistry Medium 9890998
1996 RRM2 of both TIA-1 and TIAR is the primary domain mediating specific binding to uridylate-rich RNA sequences; RRM1 does not bind RNA due to negatively charged residues in the RNP1 octamer; RRM3 binds a broad population of cellular RNAs but not uridylate-rich sequences selected by full-length protein. Affinity for selected RNA increases when RRM2 is expressed with RRM1 and RRM3 (Kd ~20 nM) vs. RRM2 alone (Kd ~50 nM). In vitro selection/amplification (SELEX) from random RNA pools, filter binding assays, domain deletion/mutant expression The Journal of biological chemistry High 8576255
2011 Upon amino acid starvation, TIA-1 and TIAR assemble onto the 5' ends of 5'TOP mRNAs and arrest translation at the initiation step, causing polysome release and accumulation of 5'TOP mRNAs in stress granules; this requires GCN2 kinase activation and mTOR pathway inactivation. RNA immunoprecipitation, polysome profiling, siRNA knockdown, luciferase reporter assays, stress granule imaging Genes & development High 21979918
1998 TIAR is essential for primordial germ cell (PGC) survival; TIAR-deficient mice fail to develop spermatogonia or oogonia due to reduced PGC survival after migration to the genital ridge by E11.5, with complete PGC absence by E13.5. TIAR-deficient embryonic stem cells also fail to proliferate without exogenous LIF in methylcellulose culture. TIAR knockout mouse generation, embryo histology, timed developmental analysis, in vitro methylcellulose colony assay Proceedings of the National Academy of Sciences of the United States of America High 9482885
2002 TIAR (p42) specifically binds the 3' terminal stem-loop of West Nile virus minus-strand RNA (WNV 3'(-)SL RNA) via RRM2 with Kd ~15 nM; TIA-1 also binds but with ~7-fold lower affinity (Kd ~112 nM). WNV replication is less efficient in TIAR knockout cells, and reconstitution with TIAR partially restores WNV growth, indicating a functional role for TIAR in WNV replication. RNA affinity column purification, peptide sequencing, UV cross-linking/immunoprecipitation, competition gel mobility shift assay, recombinant protein binding, TIAR knockout cell lines with virus growth assay and reconstitution Journal of virology High 12414941
2007 AUF1 and TIAR compete for binding to the ARE of MYC mRNA; TIAR acts as a translational suppressor of MYC, and cell proliferation levels are inversely proportional to TIAR abundance. Altering association of one ARE-binding protein with MYC mRNA reciprocally affects the other's association; genetic experiments show AUF1 and TIAR control proliferation through a MYC-dependent pathway. RNA immunoprecipitation, reporter assays, siRNA knockdown/overexpression, cell proliferation assays, mRNA abundance measurements Nature structural & molecular biology High 17486099
2006 TIAR selectively binds the 3'UTRs of mRNAs encoding translation factors (eIF4A, eIF4E, eEF1B) and c-Myc and potently suppresses their translation, particularly in response to UVC irradiation; siRNA silencing of TIAR significantly relieves UVC-induced global translational inhibition. RNA immunoprecipitation, reporter assays, siRNA knockdown, polysome profiling, UV irradiation stress assay Molecular and cellular biology High 16537914
1995 TIAR is concentrated in the nucleus of hematopoietic and nonhematopoietic cells under normal conditions, but translocates from nucleus to cytoplasm within 30 min of Fas ligation during apoptosis, preceding the onset of DNA fragmentation; this redistribution is specific to apoptosis and not observed during mitogen-induced activation. Immunofluorescence, subcellular fractionation, Western blot, Fas-mediated apoptosis induction, time-course analysis Proceedings of the National Academy of Sciences of the United States of America High 7533298
2001 TIAR activates splicing of alternative exons with weak 5' splice sites followed by U-rich stretches, including autoregulatory exons on the TIAR and TIA-1 pre-mRNAs; TIA-1 directly activates TIAR alternative exon 5' splice sites in vitro requiring a downstream U-rich stretch of at least 10 residues. TIAR overexpression induces use of cryptic 5' splice sites that are also followed by U-rich sequences when the native U-rich stretch is deleted. Overexpression in cells, in vitro splicing assays, minigene reporters, deletion mutagenesis of U-rich sequences The Journal of biological chemistry High 11514562
2008 TIA1 and TIAL1 regulate inclusion of ~15% of alternative cassette exons genome-wide via U-rich intronic motifs downstream of 5' splice sites; simultaneous knockdown of TIA1 and TIAL1 caused skipping of 88% of alternatively spliced exons associated with U-rich motifs but did not affect 97% of exons lacking such motifs; exon skipping correlated with proximity and U-richness of adjacent intronic region. Simultaneous siRNA knockdown of TIA1 and TIAL1, splicing-sensitive microarray, RT-PCR validation, bioinformatic motif analysis Genome research High 18456862
2003 TIAR binds to a U-tract sequence motif downstream of a pseudo 5' splice site within the calcitonin/CGRP intron enhancer and promotes inclusion of the alternative 3'-terminal exon >200 nt upstream; TIAR's binding depends on U1 and U6 snRNA interactions with the pseudo 5' splice site, and TIAR binding in turn promotes U6 snRNA binding (synergistic relationship). UV cross-linking, EMSA, dominant-negative TIAR mutant overexpression, minigene reporter assays, snRNA interaction analysis Molecular and cellular biology Medium 12917321
2003 TIAR, TIA-1, HuR, and hnRNP U form a multimeric protein-RNA complex that binds specifically to the first 60 nucleotides of the COX-2 mRNA 3'UTR containing multiple AUUUA sequences; insertion of this 60-nt sequence into a heterologous reporter reduces expression by 70%. EMSA, immunoprecipitation of protein-RNA complex, reporter gene assay, cytoplasmic fractionation The Journal of biological chemistry Medium 12855701
2006 Fas-activated serine/threonine kinase (FAST K) synergizes with TIAR (and TIA-1) to promote inclusion of Fas exon 6 (pro-apoptotic isoform); FAST K depletion causes Fas exon 6 skipping; in vitro phosphorylation of TIA-1 by FAST K enhances U1 snRNP recruitment without increasing TIA-1 pre-mRNA binding, connecting Fas signaling to TIAR/TIA-1-regulated splicing. siRNA depletion of FAST K, minigene reporter transfection, in vitro kinase assay with TIA-1 phosphorylation, U1 snRNP recruitment assay The Journal of biological chemistry High 17135269
2005 TIAR continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner; RRM2 and the first half of the auxiliary region are important for nuclear accumulation; RRM3 mediates nuclear export via its RNA-binding capacity; RRM2 mutations (RNP2/RNP1) redistribute TIAR to cytoplasm, while RRM3 mutations abolish nuclear export; TIAR nuclear accumulation is Ran-GTP-dependent but export is CRM1-independent. GFP-fusion domain deletion/point mutant transfection, heterokaryon nuclear export assay, transcription inhibitor treatment, Ran-GTP depletion, LMB (CRM1 inhibitor) treatment, fluorescence microscopy Journal of cell science High 16278295
2007 TIAR binds a C-rich 28-32 nt stem-loop motif (in addition to U-rich sequences) in the 3'UTRs of target mRNAs in unstressed colon cancer cells; RRM2 and RRM3 domains are sufficient for this binding (verified by surface plasmon resonance); in response to UVC stress, target mRNAs bearing C-rich motifs dissociate from TIAR and encoded protein levels increase in a TIAR-dependent manner. RNA immunoprecipitation followed by microarray (RIP-chip), surface plasmon resonance (SPR), luciferase reporter, bioinformatic motif analysis Molecular and cellular biology Medium 17682065
2002 An alternatively spliced TIAR isoform containing a 17-amino acid insert mediates translational repression of human MMP13 mRNA in human and primate cells; transient expression of this 17-aa insert reverses MMP13 mRNA silencing; co-transfection of the alternatively spliced TIAR with MMP13 in Rat2 cells suppresses MMP13 protein expression, explaining species-specific differences in MMP13 translation. Transient transfection of TIAR isoforms, Western blot for MMP13 protein, co-transfection reporter assays, species comparison The Journal of biological chemistry Medium 12426321
2007 TIAR and TIA-1 are sequestered by West Nile virus (WNV) and dengue virus replication complex components (dsRNA, NS3) in perinuclear regions of infected cells; TIAR relocation correlates with the kinetics of genomic RNA synthesis; virus infection progressively inhibits stress granule induction by arsenite and decreases processing body numbers, suggesting TIAR interaction with viral components facilitates flavivirus genome RNA synthesis and suppresses SG-mediated host translation shutoff. Immunofluorescence colocalization in infected cells, kinetic analysis, arsenite SG induction assay, processing body quantification, TIAR knockout cells Proceedings of the National Academy of Sciences of the United States of America Medium 17502609
2005 TIAR binds single-stranded thymidine-rich (T-rich) DNA sequences with ~6-fold higher affinity than equivalent RNA sequences (Kd ~1.6 nM for DNA vs ~9.4 nM for RNA); the high-affinity DNA-binding site maps to RRM2, though RRM1 alone can also bind DNA; TIAR cannot bind double-stranded DNA; TIAR can be displaced from ssDNA by active transcription through the binding site. UV cross-linking, EMSA, filter binding assays with truncation mutants, affinity measurements, in vitro transcription displacement assay Nucleic acids research High 16091628
2011 TIAR and HuR both bind U-rich and AU-rich RNA with nanomolar affinity (higher for U-rich); TIAR binds deoxy-oligonucleotides with nanomolar affinity while HuR affinity for DNA is reduced to micromolar; TIAR binding depends less on 2'-hydroxyl of RNA than HuR; SAXS data indicate that the first two domains of TIAR adopt a flexible elongated shape upon RNA binding rather than the compact shape of Hu proteins, revealing fundamentally different binding modes. Surface plasmon resonance (SPR), small-angle X-ray scattering (SAXS), comparative binding with DNA/RNA variants Nucleic acids research High 21233170
2013 RRM2 of TIAR together with its six-residue C-terminal linker extension constitutes the major high-affinity (nM) RNA- and DNA-binding module; RRM1 alone shows preferred DNA over RNA binding; NMR spectroscopy identified specific amino acid residues in RRM2 involved in AU-rich RNA binding; high-affinity U-rich RNA and T-rich DNA binding (nM) requires RRM2 plus the linker, not RRM2 alone. Surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) spectroscopy, domain truncation analysis RNA biology High 23603827
2003 DT40 cells require either TIA-1 or TIAR for viability; TIA-1 overexpression in tia-1-/-tiar-/+ cells induces efficient splicing of two TIAR alternative exons containing in-frame stop codons, reducing TIAR levels via nonsense-mediated mRNA decay, revealing a cross-regulatory mechanism where TIA-1 controls TIAR levels through splicing-coupled NMD. Conditional gene disruption in DT40 cells, RT-PCR for alternative splicing, cycloheximide treatment (NMD assay), TIA-1 expression rescue The Journal of biological chemistry High 12533540
2010 Under acute/severe hypoxia, TIAR and TIA-1 co-aggregate into stress granules (positive for eIF3η) and simultaneously suppress HIF-1α expression; silencing of TIAR (and TIA-1) upregulates HIF-1α; TIAR acts via a 3'UTR ARE of HIF-1α mRNA to suppress its expression as shown by luciferase reporter assays with the HIF-1α 3'UTR. Immunostaining, subcellular fractionation, siRNA knockdown, Western blot, luciferase reporter with HIF-1α 3'UTR ARE, immunohistochemistry of tumor xenografts Journal of molecular cell biology Medium 20980400
2018 TIAR is essential for the G2/M checkpoint; TIAR accumulates in nuclear foci called G2/M transition granules (GMGs) in late G2 and prophase, particularly under replication stress; GMGs contain CDK1 along with replication stress response and RNA metabolism proteins; TIAR retains CDK1 in GMGs and attenuates CDK1 activity; TIAR depletion accelerates mitotic entry and causes chromosomal instability under replication stress, which is alleviated by Cdc25B depletion or CDK1 inhibition. siRNA knockdown, immunofluorescence microscopy, cell cycle analysis (flow cytometry), CDK1 activity assay, chromosomal instability assay, epistasis with Cdc25B depletion and CDK1 inhibitor EMBO reports High 30538118
2009 TIAR colocalizes with mutant SOD1 in insoluble aggregates/inclusions in mouse spinal cord and glioma cells; this colocalization is abolished by RNase treatment, indicating it is RNA-mediated; mutant SOD1 expression causes significant loss of VEGF mRNA binding to TIAR, depletion of HuR from polysomes, and reduced VEGF mRNA half-life. Co-immunoprecipitation with RNase treatment, RNA immunoprecipitation (RIP), immunofluorescence, polysome fractionation, mRNA half-life assay The Journal of biological chemistry Medium 19805546
2014 In BCR-ABL1 (CML) leukemia cells, ER stress promotes cytosolic localization of TIAR, its binding to BRCA1 mRNA 3'UTR ARE, and formation of a TIAR-HuR complex; TIAR negatively regulates BRCA1 mRNA translation (shown by polysome profiling and luciferase-BRCA1 3'UTR reporter); silencing of TIAR strongly elevates BRCA1 protein levels. Polysome profiling, luciferase reporter with BRCA1 3'UTR, RNA immunoprecipitation, siRNA knockdown, subcellular fractionation Cell cycle (Georgetown, Tex.) Medium 25483082
2023 In vivo PAR-CLIP of mouse liver TIAL1 identified Insig2 and ApoB as prominent TIAL1 target transcripts; TIAL1 influences their translation in hepatocytes; Tial1 mutant mice exhibit altered cholesterol synthesis, APOB secretion, and plasma cholesterol levels, placing TIAL1 in the negative feedback regulation of cholesterol biosynthesis. In vivo PAR-CLIP (viP-CLIP) in mouse liver, translation assay in hepatocytes, Tial1 mutant mice with cholesterol/APOB phenotyping Nature communications High 37296170
2023 TIAR binds the 5' stem-loop (ε) of HBV pregenomic RNA (pgRNA) and promotes HBV DNA replication; TIAR increases translation of the polymerase (Pol) while decreasing translation of core protein (Cp) from the same pgRNA template; HBV replication or Cp expression induces TIAR redistribution from nucleus to cytoplasm. RNA immunoprecipitation, pulldown assay, Ribo-seq, PRM-based mass spectrometry, loss- and gain-of-function genetic analysis Signal transduction and targeted therapy High 37699883
2022 In pro-B cells, TIA1 and TIAL1 act redundantly as global splicing regulators controlling hundreds of mRNAs; they bind 5' splice sites for exon definition and splicing of DNA damage repair genes (including Chek2 and Rif1); in their absence, pro-B cells show exacerbated DNA damage, altered p53 expression, and increased cell death. Conditional double knockout in pro-B cells, RNA-seq, iCLIP, RT-PCR splicing validation, DNA damage markers (γH2AX), flow cytometry Cell reports High 36543128
2023 TIA1 and TIAL1 are required for germinal center (GC) B cell survival and differentiation; they control Mcl1 mRNA translation to promote expression of the prosurvival molecule MCL1; TIA1/TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection, expansion, and differentiation into high-affinity antibody-producing clones. Conditional double knockout mice, GC B cell phenotyping by flow cytometry, polysome profiling for MCL1 translation, Western blot Cellular & molecular immunology High 37474714
2025 TIAL1 directly interacts with the core Hippo pathway component SAV1 (protein-protein interaction), disrupting the MST1-SAV1 interaction, thereby suppressing Hippo signaling and activating YAP; this function is independent of TIAL1's RNA-binding activity, as RNA-binding-deficient mutants still interact with SAV1 and suppress Hippo; TIAL1 expression is upregulated by energy surplus and EGF. Co-immunoprecipitation, domain mutant analysis (RNA-binding deficient mutants), YAP activity reporter, MST1-SAV1 interaction assay, loss/gain-of-function in hepatocellular carcinoma cells Oncogene Medium 42032365
2025 The first 23 nucleotides of the TIAR 5'UTR are both necessary and sufficient to confer resistance to SARS-CoV-2 Nsp1-mediated translation shutoff; the absence of guanosines within positions 10-18 downstream from the 5' end is a defining sequence feature (not secondary structure) shared between the SARS-CoV-2 leader and the TIAR 5'UTR that confers Nsp1 resistance. Reporter shutoff assays with 5'UTR truncation and mutation constructs in cells expressing Nsp1 RNA (New York, N.Y.) Medium 41407513
2025 Hypoxia-induced lactylation of HMGB1 at K177 drives nuclear export of HMGB1 in a complex with TIAR, promoting stress granule formation in the cytosol; K177R mutation of HMGB1 completely blocks HMGB1-TIAR complex export and subsequent SG formation; other stressors (arsenite, heat shock) trigger TIAR nuclear export and SG assembly independently of HMGB1. Mass spectrometry of HMGB1 lactylation sites, K-to-R mutant transfection, co-immunoprecipitation of HMGB1-TIAR complex, immunofluorescence for SG formation Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40788094
2014 TIAR (and TIA-1) bind SIRT1 pre-mRNA and regulate its alternative splicing; TIAL1 knockdown inhibits exon 8 exclusion (decreasing SIRT1-ΔExon8 levels), while HuR promotes exon 8 exclusion, revealing antagonistic regulation of SIRT1 splicing between these two RBPs. siRNA knockdown of TIA1/TIAL1 and HuR, RT-PCR for SIRT1 splice variants, reporter assays International journal of molecular sciences Medium 24566137
2009 TIA-1 and TIAR binding sites on the WNV 3'(-)SL RNA were mapped to short AU sequences (UAAUU) in two internal loops; mutations that reduce TIAR/TIA-1 binding efficiency progressively decrease intracellular genomic RNA levels and virus production without affecting translation efficiency of mutant RNAs; several mutants rapidly reverted in vivo, indicating TIAR/TIA-1 interaction facilitates asymmetric amplification of genome RNA from the minus-strand template. Infectious clone mutagenesis, in vitro binding assays, plaque assays, intracellular RNA quantification, reversion analysis Journal of virology High 18768985

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. The Journal of cell biology 1074 10613902
2007 Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly. Proceedings of the National Academy of Sciences of the United States of America 255 17502609
1999 Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. The Journal of biological chemistry 228 9890998
1996 Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities. The Journal of biological chemistry 196 8576255
2011 Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR. Genes & development 182 21979918
1998 RNA-binding protein TIAR is essential for primordial germ cell development. Proceedings of the National Academy of Sciences of the United States of America 162 9482885
2007 Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation. Nature structural & molecular biology 156 17486099
2002 Cell proteins TIA-1 and TIAR interact with the 3' stem-loop of the West Nile virus complementary minus-strand RNA and facilitate virus replication. Journal of virology 156 12414941
2006 Translational repression by RNA-binding protein TIAR. Molecular and cellular biology 130 16537914
2003 The proximal region of the 3'-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. The Journal of biological chemistry 123 12855701
2001 TIA-1 and TIAR activate splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on their own pre-mRNAs. The Journal of biological chemistry 115 11514562
1995 The RNA-binding protein TIAR is translocated from the nucleus to the cytoplasm during Fas-mediated apoptotic cell death. Proceedings of the National Academy of Sciences of the United States of America 114 7533298
2005 IL-1beta induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3' untranslated region: Involvement of divergent RNA-binding factors HuR, KSRP and TIAR. International journal of cancer 94 15514971
2002 Sendai virus trailer RNA binds TIAR, a cellular protein involved in virus-induced apoptosis. The EMBO journal 94 12356730
2008 A systematic analysis of intronic sequences downstream of 5' splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation. Genome research 87 18456862
1996 Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR. Nucleic acids research 86 8871565
2006 Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing. The Journal of biological chemistry 72 17135269
2005 Identification of the sequence determinants mediating the nucleo-cytoplasmic shuttling of TIAR and TIA-1 RNA-binding proteins. Journal of cell science 71 16278295
2004 Herpes simplex virus 1 induces cytoplasmic accumulation of TIA-1/TIAR and both synthesis and cytoplasmic accumulation of tristetraprolin, two cellular proteins that bind and destabilize AU-rich RNAs. Journal of virology 71 15280467
2007 Elucidation of a C-rich signature motif in target mRNAs of RNA-binding protein TIAR. Molecular and cellular biology 70 17682065
2003 U1 snRNP-dependent function of TIAR in the regulation of alternative RNA processing of the human calcitonin/CGRP pre-mRNA. Molecular and cellular biology 64 12917321
2016 LncRNA MT1JP functions as a tumor suppressor by interacting with TIAR to modulate the p53 pathway. Oncotarget 60 26909858
2009 Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor. The Journal of biological chemistry 58 19805546
2005 Novel DNA-binding properties of the RNA-binding protein TIAR. Nucleic acids research 58 16091628
2019 Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules. Neuron 57 31378567
2011 Different modes of interaction by TIAR and HuR with target RNA and DNA. Nucleic acids research 57 21233170
2002 Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR). The Journal of biological chemistry 55 12426321
2014 Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation. Cell cycle (Georgetown, Tex.) 51 25483082
2008 Mutation of mapped TIA-1/TIAR binding sites in the 3' terminal stem-loop of West Nile virus minus-strand RNA in an infectious clone negatively affects genomic RNA amplification. Journal of virology 45 18768985
2010 TIAR and TIA-1 mRNA-binding proteins co-aggregate under conditions of rapid oxygen decline and extreme hypoxia and suppress the HIF-1α pathway. Journal of molecular cell biology 40 20980400
2016 The Stress Granule RNA-Binding Protein TIAR-1 Protects Female Germ Cells from Heat Shock in Caenorhabditis elegans. G3 (Bethesda, Md.) 38 26865701
2014 HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA. International journal of molecular sciences 31 24566137
2003 TIA-1 or TIAR is required for DT40 cell viability. The Journal of biological chemistry 31 12533540
2006 Control of the ATP synthase beta subunit expression by RNA-binding proteins TIA-1, TIAR, and HuR. Biochemical and biophysical research communications 27 16890199
2013 Distinct binding properties of TIAR RRMs and linker region. RNA biology 26 23603827
2000 Expression of the RNA-binding protein TIAR is increased in neurons after ischemic cerebral injury. Journal of neuroscience research 24 10700014
2021 LOXL1-AS1 communicating with TIAR modulates vasculogenic mimicry in glioma via regulation of the miR-374b-5p/MMP14 axis. Journal of cellular and molecular medicine 23 34890108
2010 Impaired embryonic development in mice overexpressing the RNA-binding protein TIAR. PloS one 23 20596534
2021 PHAROH lncRNA regulates Myc translation in hepatocellular carcinoma via sequestering TIAR. eLife 18 34002693
2023 The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis. Cellular & molecular immunology 17 37474714
2022 The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis. Cell reports 17 36543128
2013 The C. elegans TIA-1/TIAR homolog TIAR-1 is required to induce germ cell apoptosis. Genesis (New York, N.Y. : 2000) 17 23913578
2018 TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress. EMBO reports 16 30538118
2023 RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation. Signal transduction and targeted therapy 13 37699883
2014 The involvement of mRNA processing factors TIA-1, TIAR, and PABP-1 during mammalian hibernation. Cell stress & chaperones 13 24590458
2018 miR‑223‑3p/TIAL1 interaction is involved in the mechanisms associated with the neuroprotective effects of dexmedetomidine on hippocampal neuronal cells in vitro. Molecular medicine reports 12 30569136
2016 PTB and TIAR binding to insulin mRNA 3'- and 5'UTRs; implications for insulin biosynthesis and messenger stability. Heliyon 12 27699280
2014 Genome-wide profiling reveals a role for T-cell intracellular antigens TIA1 and TIAR in the control of translational specificity in HeLa cells. The Biochemical journal 12 24927121
2005 The RNA binding protein TIAR is involved in the regulation of human iNOS expression. Cellular and molecular biology (Noisy-le-Grand, France) 12 16191398
2023 In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion. Nature communications 10 37296170
2015 TIA-1 and TIAR interact with 5'-UTR of enterovirus 71 genome and facilitate viral replication. Biochemical and biophysical research communications 10 26363455
1998 Increased expression of the TIAR protein in the hippocampus of Alzheimer patients. Neuroreport 9 9631446
2009 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. Journal of virology 8 19339348
2023 TIAR and FMRP shape pro-survival nascent proteome of leukemia cells in the bone marrow microenvironment. iScience 7 37123244
2016 Genome-wide analysis of TIAR RNA ligands in mouse macrophages before and after LPS stimulation. Genomics data 7 26981431
2015 Targeted Knockdown of RNA-Binding Protein TIAR for Promoting Self-Renewal and Attenuating Differentiation of Mouse Embryonic Stem Cells. Stem cells international 7 25918534
2010 Identification of chosen apoptotic (TIAR and TIA-1) markers expression in thyroid tissues from adolescents with immune and non-immune thyroid diseases. Folia histochemica et cytobiologica 7 20675271
2025 Lactylation of HMGB1 at K177 Drives Nuclear Export of TIAR to Promote Hypoxia-Induced Stress Granule Formation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40788094
2022 The TIAR-mediated Nrf2 response to oxidative stress is mediated through the Nrf2 noncoding 3'untranslated region in Spodoptera litura. Free radical biology & medicine 6 35367339
2023 The stress granule component TIAR during the non-embryonic development of the colonial ascidian Botryllusschlosseri. Fish & shellfish immunology 5 37604264
2021 MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways. Technology in cancer research & treatment 5 33896245
2023 Depletion of TIAR impairs embryogenesis via inhibiting zygote genome transcribe. Reproduction in domestic animals = Zuchthygiene 3 37667420
2023 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. Frontiers in cell and developmental biology 3 38161334
2026 Escape from SARS-CoV-2 Nsp1-mediated host shutoff by TIAR transcript reveals general features of Nsp1 resistance. RNA (New York, N.Y.) 1 41407513
2026 TIAL1 regulates the Hippo pathway through an RNA-binding-independent mechanism. Oncogene 0 42032365

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