TIAL1 encodes TIAR, a ubiquitously expressed nucleocytoplasmic RNA-binding protein with three RNA recognition motifs and a glutamine-rich low-complexity C terminus. It preferentially recognizes uridine-rich RNA through RRM2, regulates alternative splice-site choice at weak 5-prime splice sites, and binds AU-rich elements in selected mRNA 3-prime UTRs to repress translation or recruit post-transcriptional regulatory machinery. Under environmental stress, TIAL1 redistributes from the nucleus to cytoplasmic stress granules and helps recruit untranslated mRNPs. Direct biochemistry also demonstrates T-rich single-stranded DNA binding, while historical work proposed a context-specific cytolytic-granule nucleolysin role.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0035925 mRNA 3'-UTR AU-rich region binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference assigns specific binding to AU-rich regions in mRNA 3-prime UTRs. Reason: Direct biochemical and cellular studies show that human TIAR binds AU-rich 3-prime UTR elements in TNF and GADD45A mRNAs. This is a defining molecular activity underlying selective post-transcriptional regulation. Supporting Evidence: PMID:9890998 Here, we report the identification of the RNA-binding protein TIAR as a protein involved in complex 1. file:human/TIAL1/TIAL1-deep-research-manual.md The best-supported core picture is therefore a U-rich RNA recognition protein |
| GO:0140517 protein-RNA adaptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference assigns an ancestral protein-RNA adaptor activity. Reason: Rox8 recruits miRNA-loaded RISC to yki mRNA, and human TIAR substitutes in the fly assay and destabilizes YAP mRNA in human cells. Together with the IBA, this supports a possible conserved adaptor-like role. The direct human partner architecture has not been established, so the annotation is retained as contextual rather than treated as a core molecular function. Supporting Evidence: PMID:33203680 TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP mRNA in human cells. |
| GO:0000381 regulation of alternative mRNA splicing, via spliceosome | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference assigns regulation of spliceosomal alternative splicing. Reason: This is a core TIAL1 function. Human depletion changes endogenous TIA1 isoform output, and joint TIA1/TIAL1 perturbation demonstrates regulation of weak splice sites adjacent to U-rich intronic enhancers. Supporting Evidence: PMID:17488725 TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro maps the RRM architecture to the generic nucleic-acid-binding parent term. Reason: The parent is technically true but too broad to convey TIAL1's defining activity. Direct studies establish RNA binding, with a strong preference for uridylate-rich sequences, so the informative replacement is RNA binding. Proposed replacements: RNA binding Supporting Evidence: PMID:8576255 it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro propagates DNA binding from the TIAR RRM2 family signature. Reason: Direct UV-crosslinking and mobility-shift assays verify high-affinity binding of recombinant TIAR to T-rich single-stranded DNA. This is real but secondary to the dominant RNA-processing functions, and its in vivo scope remains unresolved. Supporting Evidence: PMID:16091628 TIAR had a nearly 6-fold greater affinity for DNA than RNA |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro assigns RNA binding from the three-RRM architecture. Reason: RNA binding is the fundamental molecular activity of TIAL1 and is established by direct biochemical specificity measurements and multiple human mRNA-interactome datasets. |
| GO:0003730 mRNA 3'-UTR binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA predicts binding to mRNA 3-prime UTRs. Reason: Direct studies show binding of TIAR to the 3-prime UTRs of TNF, GADD45A, translation-factor mRNAs, and YAP. The broader term is correct alongside the more specific AU-rich-region term. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation places TIAL1 in the nucleus. Reason: Direct human-cell imaging shows that TIA1 and TIAR are concentrated in the nucleus at steady state, consistent with their nuclear splicing role. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation places TIAL1 in the cytoplasm. Reason: TIAL1 shuttles into the cytoplasm and directly accumulates there during stress, where it binds 3-prime UTRs, represses translation, and enters stress granules. |
| GO:0010494 cytoplasmic stress granule | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt location mapping places TIAL1 in cytoplasmic stress granules. Reason: Direct human-cell microscopy shows stress-dependent colocalization of TIA1/TIAR with polyadenylated untranslated RNA in cytoplasmic stress granules. Supporting Evidence: PMID:10613902 TIA-1 and TIAR colocalize with poly(A)(+) RNA at cytoplasmic foci that resemble the stress granules |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | MODIFY | Summary: ARBA predicts a broad role in regulation of cell proliferation. Reason: The Rox8/TIAR study supports a directional effect through YAP/yki mRNA destabilization and suppression of tissue overgrowth. The existing experimentally supported negative-regulation term is more informative than this undirected parent. Proposed replacements: negative regulation of cell population proliferation |
| GO:0044194 cytolytic granule | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt maps the historical TIAR location statement to cytolytic granule. Reason: The founding paper identified a lysosome-targeting motif and interpreted TIAR as probably cytotoxic-granule associated. This is a specialized historical localization rather than the ubiquitous protein's defining location, but it is not contradicted. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: BioPlex reports a candidate TIAL1-DZIP3 co-association. Reason: The large-scale co-association may be real, but generic protein binding does not describe a useful molecular activity and the screen does not establish the functional consequence of this interaction. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: BioPlex 3.0 reports a candidate TIAL1-DZIP3 co-association. Reason: The cell-line-specific co-association may be real, but generic protein binding is uninformative and no mechanism-specific GO molecular function is justified by this screen. |
| GO:0005515 protein binding | IPI PMID:34517762 MOV10 Helicase Interacts with Coronavirus Nucleocapsid Prote... | MARK AS OVER ANNOTATED | Summary: Endogenous TIAR and MOV10 co-immunoprecipitate in human cells. Reason: The endogenous association is directly supported, including in uninfected cells, but protein binding is too generic. The paper does not isolate a specific TIAL1 molecular activity attributable to MOV10 association. Supporting Evidence: PMID:34517762 An interaction between endogenous MOV10 and the SG component TIAR was also identified, even in mock-infected cells. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence detects TIAL1 in nucleoplasm. Reason: Nucleoplasm is the informative steady-state nuclear location for TIAL1's alternative-splicing activity and is consistent with direct microscopy and Reactome pathway context. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence detects TIAL1 in cytosol. Reason: Cytosolic localization is consistent with direct 3-prime-UTR translation regulation and stress-dependent recruitment to cytoplasmic granules. |
| GO:0005634 nucleus | EXP PMID:10613902 RNA-binding proteins TIA-1 and TIAR link the phosphorylation... | ACCEPT | Summary: Direct human-cell experiments place TIAR predominantly in the nucleus at steady state. Reason: The paper distinguishes TIAR from TIA1 with specific antibodies and shows nuclear concentration before stress-induced redistribution. Supporting Evidence: PMID:10613902 TIA-1 and TIAR are concentrated in the nuclei of the DU145 human prostate cell line |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed transfer from mouse Tial1 assigns cytoplasmic localization. Reason: The orthology transfer is sound and independently corroborated by direct human-cell studies showing cytoplasmic redistribution of TIAR under stress. |
| GO:0044194 cytolytic granule | EXP PMID:1326761 Identification and functional characterization of a TIA-1-re... | KEEP AS NON CORE | Summary: The founding study proposed TIAR as a cytotoxic-granule-associated nucleolysin. Reason: The paper's motif and fractionation context support a specialized cytolytic-granule assignment, but the cached source is abstract-only and the localization is not central to the ubiquitous RNA regulatory role. Supporting Evidence: PMID:1326761 The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein. |
| GO:0140517 protein-RNA adaptor activity | IDA PMID:33203680 Rox8 promotes microRNA-dependent yki messenger RNA decay. | KEEP AS NON CORE | Summary: Human TIAR functionally substitutes for Rox8 in a target-RNA/RISC regulatory mechanism. Reason: The full FlyBase curation is experimental, and the abstract confirms that human TIAR promotes yki degradation in flies and destabilizes YAP mRNA in human cells. This supports a conserved regulatory role, but does not directly identify the human protein partner bridged to the target RNA; retain the experimental annotation without elevating it to a core molecular function. Supporting Evidence: PMID:33203680 Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC |
| GO:0003730 mRNA 3'-UTR binding | IDA PMID:33203680 Rox8 promotes microRNA-dependent yki messenger RNA decay. | ACCEPT | Summary: The Rox8/TIAR study assigns direct 3-prime-UTR binding. Reason: Curated full-text evidence supports the annotation, and independent human studies directly demonstrate TIAR binding to GADD45A, TNF, and other mRNA 3-prime UTRs. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:33203680 Rox8 promotes microRNA-dependent yki messenger RNA decay. | KEEP AS NON CORE | Summary: Rox8/TIAR activity suppresses Hippo-dependent tissue overgrowth. Reason: The phenotype is supported by genetic perturbation and human TIAR complementation, but reduced proliferation is a downstream, context-specific consequence of YAP/yki post-transcriptional regulation rather than TIAL1's defining molecular role. |
| GO:0035332 positive regulation of hippo signaling | IMP PMID:33203680 Rox8 promotes microRNA-dependent yki messenger RNA decay. | KEEP AS NON CORE | Summary: Rox8/TIAR-mediated yki/YAP mRNA destabilization increases Hippo-pathway output. Reason: The paper directly supports this directional pathway consequence, but the result is target- and context-specific. The core activity is 3-prime-UTR recognition coupled to post-transcriptional silencing. |
| GO:2000637 positive regulation of miRNA-mediated gene silencing | IGI PMID:33203680 Rox8 promotes microRNA-dependent yki messenger RNA decay. | KEEP AS NON CORE | Summary: Rox8 stabilizes miR-8-loaded RISC targeting of yki mRNA, and human TIAR functionally complements this mechanism. Reason: Genetic interaction and human complementation support the process, but the detailed miRNA mechanism was established in Drosophila and remains a specialized target-specific role in the human review. Supporting Evidence: PMID:33203680 recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6803527 | ACCEPT | Summary: Reactome places TIAL1 in the nucleoplasmic FGFR2 alternative-splicing reaction context. Reason: The localization is consistent with direct imaging and TIAL1's nuclear splicing role. Reactome appropriately notes that the precise contribution to FGFR2 IIIb choice is not fully resolved. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | ACCEPT | Summary: UV-crosslinking interactome capture identifies TIAL1 in the human mRNA-bound proteome. Reason: The high-throughput direct RNA-association evidence independently confirms the well-established RRM-mediated RNA-binding activity. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | ACCEPT | Summary: An independent UV-crosslinking/oligo-dT proteome study identifies TIAL1 as mRNA bound. Reason: This independent high-throughput dataset corroborates direct mRNA binding, which is already supported by targeted biochemical studies. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed transfer from mouse Tial1 assigns nuclear localization. Reason: The transfer is consistent with direct human-cell imaging and the conserved nuclear alternative-splicing role. |
| GO:0010494 cytoplasmic stress granule | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed orthology transfer assigns stress-granule localization. Reason: The transfer is independently corroborated by direct human-cell microscopy showing stress-dependent TIAR accumulation with untranslated polyadenylated RNA. |
| GO:0006952 defense response | TAS PMID:1326761 Identification and functional characterization of a TIA-1-re... | MARK AS OVER ANNOTATED | Summary: The founding paper proposed TIAR as a candidate cytotoxic-lymphocyte nucleolysin. Reason: Recombinant TIAR fragmented DNA in permeabilized targets, but this assay and candidate-effector interpretation do not establish a normal broad defense-response role for TIAL1. The more specific specialized localization is retained separately. Supporting Evidence: PMID:1326761 Our data suggest that the granules of CTLs contain at least two candidate nucleolysins involved in CTL killing. |
| GO:0003723 RNA binding | TAS PMID:1326761 Identification and functional characterization of a TIA-1-re... | ACCEPT | Summary: The founding sequence study identifies three RNA-binding domains in TIAR. Reason: RNA binding is strongly corroborated by later direct biochemical studies that define uridylate specificity and the dominant role of RRM2. |
| GO:0005764 lysosome | TAS PMID:1326761 Identification and functional characterization of a TIA-1-re... | MODIFY | Summary: A lysosome-targeting motif was used to infer granule localization. Reason: The study interprets this motif in the specific context of cytotoxic granules, which are lysosome-related organelles. Generic lysosome is broader than the paper's claim; cytolytic granule is the appropriate replacement. Proposed replacements: cytolytic granule Supporting Evidence: PMID:1326761 The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein. |
| GO:0006357 regulation of transcription by RNA polymerase II | TAS PMID:9207209 An alternative form of nucleolysin binds to a T-cluster DNA ... | KEEP AS NON CORE | Summary: An alternative T-cluster-binding product represses a PF4 promoter reporter. Reason: The reporter result supports transcriptional regulation through T-rich promoter binding, and modern biochemistry confirms direct TIAR DNA binding. However, the old alternative product is absent from current UniProt isoforms and this is not a defining TIAL1 role. Supporting Evidence: PMID:9207209 Co-transfection experiments showed that TCBP reduced the gene expression from the PF4 promoter. |
| GO:0006915 apoptotic process | TAS PMID:1326761 Identification and functional characterization of a TIA-1-re... | MARK AS OVER ANNOTATED | Summary: Recombinant TIAR induces DNA fragmentation in permeabilized target cells. Reason: The biochemical result is reproducible evidence of nucleolytic potential, but a permeabilized-cell assay does not establish that endogenous TIAL1 normally executes or broadly regulates apoptosis. Its RNA-regulatory effects on survival are target and context dependent. Supporting Evidence: PMID:1326761 Like TIA-1, purified recombinant TIAR induced DNA fragmentation in permeabilized target cells. |
| GO:0017148 negative regulation of translation | IMP PMID:16537914 Translational repression by RNA-binding protein TIAR. | NEW | Summary: TIAL1 silencing relieves stress-induced global translation inhibition in human cells. Reason: Direct target-binding and translation assays show that TIAR represses multiple translation-factor mRNAs, while TIAL1 silencing functionally relieves UVC-induced translation inhibition. This missing term captures a central cytoplasmic activity. Supporting Evidence: PMID:16537914 The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression. |
| GO:0034063 stress granule assembly | IDA PMID:10613902 RNA-binding proteins TIA-1 and TIAR link the phosphorylation... | NEW | Summary: TIA1 and TIAR recruit untranslated mRNAs into mammalian stress granules. Reason: Direct human-cell imaging and dominant-negative perturbation establish TIA1/TIAR-dependent routing of untranslated mRNPs into stress granules. This process term complements, rather than duplicates, the existing cellular-component annotations. Supporting Evidence: PMID:10613902 TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2Ξ± to promote the recruitment of untranslated mRNAs to SGs. |
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Download this section (compressed HTML)Q: Does the RRM1 insertion in TIAL1 isoform 2 alter RNA target choice, DNA binding, nucleocytoplasmic shuttling, or stress-granule condensation?
Q: How broadly does human TIAL1 recruit miRNA/RISC machinery beyond the demonstrated YAP/yki context?
Q: Is TIAL1 independently required for particular classes of stress granules, or is it functionally redundant with TIA1 and G3BP proteins?
Q: Is the historical TCBP product expressed from the modern TIAL1 locus, and does TIAL1 regulate transcription through DNA binding in vivo?
Q: Does endogenous TIAL1 enter cytolytic granules and contribute directly to cytotoxic-lymphocyte target killing?
Experiment: Perform isoform-resolved eCLIP, quantitative DNA/RNA binding, and matched rescue of splicing and translation reporters after endogenous TIAL1 depletion.
Hypothesis: The RRM1 insertion in isoform 2 changes a subset of TIAL1 RNA and DNA targets without disrupting the dominant RRM2-mediated U-rich specificity.
Type: Isoform-resolved target mapping and functional rescue
Experiment: Use rapid degron-mediated single and combinatorial depletion of TIAL1, TIA1, G3BP1, and G3BP2, followed by endogenous live imaging and granule RNA profiling across oxidative, heat, osmotic, and UV stress.
Hypothesis: TIAL1 is conditionally required for assembly of specific stress-granule subclasses when TIA1/G3BP nucleation capacity is limiting.
Type: Genetic epistasis and live-cell condensate analysis
Experiment: Combine AGO2/TIAL1 co-immunoprecipitation, eCLIP, miRNA perturbation, and target 3-prime-UTR reporters with TIAL1 wild-type and adaptor-defective rescue.
Hypothesis: Human TIAL1 recruits RISC to a defined subset of 3-prime-UTR targets in addition to YAP.
Type: RNP mapping and reporter epistasis
Experiment: Map endogenous chromatin association with orthogonal nuclease-based and crosslinking assays, perturb transcription, and compare DNA occupancy with nascent RNA binding and splice-site changes.
Hypothesis: DNA binding positions TIAL1 near nascent U-rich transcripts rather than serving as a general transcription-factor activity.
Type: Chromatin-RNA coupling analysis
Experiment: Endogenously tag and acutely deplete TIAL1 in primary NK cells or CTLs, measure cytolytic-granule localization and exocytosis, and test target-cell killing with isoform-specific rescue.
Hypothesis: Cytolytic-granule localization and target-cell nucleolytic activity are specialized endogenous TIAL1 functions in human cytotoxic lymphocytes.
Type: Endogenous localization and immune-cell functional rescue
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The two current human TIAL1 isoforms have not been functionally resolved, particularly the effect of the isoform-2 insertion within RRM1.
OPEN BIOLOGY MF_DARK
What is known: UniProt defines the sequence difference, but the primary splicing, translation, DNA-binding, and stress-granule studies generally do not distinguish endogenous TIAL1 isoforms.
Significance: Isoform resolution is needed to know whether RRM1 sequence variation changes RNA/DNA specificity, target selection, localization, or condensation.
What would resolve it: Combine isoform-resolved long-read expression and eCLIP with matched isoform rescue after endogenous TIAL1 depletion.
Provenance (the field's own admissions):
Gap: TIAL1's independent requirement for stress-granule assembly is unresolved because TIA1 and G3BP-family proteins provide partly redundant nucleation activities.
OPEN BIOLOGY BP_DARK
What is known: Direct studies establish recruitment and participation, but the classic dominant-negative construct targets TIA1 and secondarily traps endogenous TIAR.
Significance: Separating recruitment from essential nucleation will clarify whether TIAL1 is a core scaffold or a condition-dependent contributor.
What would resolve it: Use acute single and combinatorial TIAL1, TIA1, G3BP1, and G3BP2 depletion with endogenous live-cell stress-granule imaging and separation-of-function rescue.
Provenance (the field's own admissions):
Gap: The physiological relevance of cytolytic-granule localization and nucleolytic activity remains uncertain.
OPEN BIOLOGY CC_DARK
What is known: The founding study used a targeting motif, fractionation context, and recombinant protein in permeabilized cells; modern endogenous, isoform-specific evidence is lacking.
Significance: Resolving this issue would distinguish a specialized immune effector role from an historical overinterpretation of biochemical activity.
What would resolve it: Endogenously tag TIAL1 in primary human cytotoxic lymphocytes, quantify granule colocalization and release, and test target-cell killing after acute TIAL1 loss with isoform rescue.
Provenance (the field's own admissions):
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