Existing Annotations Review

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-2α to promote the recruitment of untranslated mRNAs to SGs.

Core Functions

TIAL1 recognizes U-rich pre-mRNA elements through its RRM domains and promotes alternative splice-site choice at weak 5-prime splice sites in the nucleoplasm.

Molecular Function:

RNA binding

Directly Involved In:

regulation of alternative mRNA splicing, via spliceosome

Cellular Locations:

nucleoplasm

Supporting Evidence:

PMID:17488725
TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression

Cytosolic TIAL1 binds AU-rich and other regulatory elements in selected mRNA 3-prime UTRs and represses their translation, including GADD45A and mRNAs encoding translation factors.

Molecular Function:

mRNA 3'-UTR AU-rich region binding

Directly Involved In:

negative regulation of translation

Cellular Locations:

cytosol

Supporting Evidence:

PMID:16537914
TIAR bound the 3'-untranslated regions of these mRNAs and potently suppressed their translation

During environmental stress, TIAL1 relocalizes with untranslated polyadenylated mRNPs into cytoplasmic stress granules and participates in stress-granule assembly.

Molecular Function:

RNA binding

Directly Involved In:

stress granule assembly

Cellular Locations:

cytoplasmic stress granule

Supporting Evidence:

PMID:10613902
TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2α to promote the recruitment of untranslated mRNAs to SGs.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10613902

RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules.

TIA-1 and TIAR recruit untranslated mRNAs to mammalian stress granules downstream of stress-induced eIF2-alpha phosphorylation.

"TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2α to promote the recruitment of untranslated mRNAs to SGs."

PMID:1326761

Identification and functional characterization of a TIA-1-related nucleolysin.

Recombinant TIAR induces DNA fragmentation in permeabilized target cells.

"Like TIA-1, purified recombinant TIAR induced DNA fragmentation in permeabilized target cells."
A lysosome-targeting motif led the authors to propose cytotoxic-granule association.

"The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein."

PMID:8576255

Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities.

RRM2 mediates sequence-specific binding to uridylate-rich RNA.

"it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs"

PMID:9207209

An alternative form of nucleolysin binds to a T-cluster DNA in the silencer element of platelet factor 4 gene.

The alternative T-cluster-binding product binds the PF4 promoter and represses its reporter activity.

"Co-transfection experiments showed that TCBP reduced the gene expression from the PF4 promoter."

PMID:9890998

Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA.

TIAR is a component of the cytosolic protein complex bound to the TNF-alpha AU-rich element.

"Here, we report the identification of the RNA-binding protein TIAR as a protein involved in complex 1."

PMID:16091628

Novel DNA-binding properties of the RNA-binding protein TIAR.

Recombinant TIAR binds T-rich single-stranded DNA with higher apparent affinity than the corresponding RNA.

"TIAR had a nearly 6-fold greater affinity for DNA than RNA"

PMID:16537914

Translational repression by RNA-binding protein TIAR.

TIAR binds 3-prime UTRs of translation-factor mRNAs and represses their translation.

"TIAR bound the 3'-untranslated regions of these mRNAs and potently suppressed their translation"
TIAR silencing relieves UVC-induced global translation inhibition.

"The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression."

PMID:16600875

Posttranscriptional derepression of GADD45alpha by genotoxic stress.

TIAR binds the GADD45A 3-prime UTR and directly represses translation.

"TIAR potently inhibited GADD45alpha translation."

PMID:17135269

Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.

TIA1 and TIAR promote suboptimal 5-prime splice sites followed by U-rich intronic enhancers.

"TIA-1 (T-cell intracellular antigen 1) and TIAR (TIA-1-related) proteins regulate alternative pre-mRNA splicing by promoting the use of suboptimal 5' splice sites followed by uridine-rich intronic enhancer sequences."

PMID:17488725

Two isoforms of the T-cell intracellular antigen 1 (TIA-1) splicing factor display distinct splicing regulation activities. Control of TIA-1 isoform ratio by TIA-1-related protein.

TIAR depletion changes endogenous TIA1 alternative isoform output in human and mouse cells.

"TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression"

PMID:20932473

DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.

DNA damage promotes p38-dependent phosphorylation and release of TIAR from GADD45A mRNA.

"we did observe strong direct phosphorylation of TIAR by p38 in vitro"

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

Interactome capture identified a biochemically defined mammalian mRNA-bound proteome.

"We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria"

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

UV crosslinking and oligo-dT purification identified the mRNA-bound proteome of a human cell line.

"Application to a human embryonic kidney cell line identified close to 800 proteins."

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

BioPlex 2.0 produced a large candidate human protein co-association network.

"With more than 56,000 candidate interactions"

PMID:33203680

Rox8 promotes microRNA-dependent yki messenger RNA decay.

Human TIAR can promote yki degradation in flies and destabilize YAP mRNA in human cells.

"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."

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

BioPlex 3.0 generated cell-line-specific human protein co-association networks.

"These networks model the interactome whose structure encodes protein function, localization, and complex membership."

PMID:34517762

MOV10 Helicase Interacts with Coronavirus Nucleocapsid Protein and Has Antiviral Activity.

Endogenous MOV10 and TIAR co-immunoprecipitate even in uninfected human cells.

"An interaction between endogenous MOV10 and the SG component TIAR was also identified, even in mock-infected cells."

Reactome:R-HSA-6803527

ESRP1 and 2 bind FGFR2 pre-mRNA to promote FGFR2b maturation and expression

Reactome includes TIAL1 among nucleoplasmic factors contributing to FGFR2 IIIb-specific splicing.

"Other factors that appear to contribute to IIIb-specific splicing include hnRNPM, TIA1 and TIAL1"

file:human/TIAL1/TIAL1-uniprot.txt

UniProtKB record for human TIAL1 (Q01085)

TIAL1 is a reviewed 375-amino-acid protein.

"Reviewed; 375 AA."
UniProt assigns three RNA recognition motifs.

"FT DOMAIN 9..85"
UniProt records nuclear, cytoplasmic, cytolytic-granule, and stress-granule localization.

"Cytoplasm, Stress granule"

file:human/TIAL1/TIAL1-notes.md

Manual literature and annotation review notes for human TIAL1

All 35 grouped GOA annotations were manually adjudicated.

"## Existing annotation decisions"
The notes distinguish core RNA functions from historical candidate nucleolysin claims.

"## Cytolytic-granule, lysosome, defense, and apoptosis boundary"

file:human/TIAL1/TIAL1-deep-research-manual.md

Manual literature synthesis for human TIAL1 (Q01085)

The best-supported core is U-rich RNA recognition coupled to splicing, translation control, and stress-responsive mRNP partitioning.

"The best-supported core picture is therefore a U-rich RNA recognition protein"

Suggested Experiments

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

Knowledge Gaps

What is not known — 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):

"isoform 2 inserts 18 residues at canonical position 43 within RRM1" — file:human/TIAL1/TIAL1-notes.md

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):

"its dominant-negative perturbation targeted TIA1 while secondarily trapping endogenous TIAR" — file:human/TIAL1/TIAL1-notes.md

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):

"Generic lysosome is modified to the more specific cytolytic granule." — file:human/TIAL1/TIAL1-notes.md

Deep Research

Manual

(TIAL1-deep-research-manual.md)

Manual literature synthesis for human TIAL1 (Q01085) Manual

Manual literature synthesis for human TIAL1 (Q01085)

Research status

Automated deep research was attempted on 2026-07-18. Falcon failed with HTTP 402 and the Perplexity-lite fallback failed with HTTP 401. This manual synthesis uses the reviewed UniProt record, all GOA source references, additional cached primary studies, and the local Reactome record.

Synthesis

TIAL1 encodes TIAR, a 375-aa nucleocytoplasmic RNA-binding protein with three RRMs and a glutamine-rich low-complexity C terminus. RRM2 provides the dominant sequence-specific recognition of uridylate-rich RNA, while the other RRMs contribute affinity or additional contacts. This molecular specificity supports two central nuclear and cytoplasmic programs.

In the nucleus, TIAL1 binds U-rich intronic elements downstream of weak 5-prime splice sites and regulates alternative splice-site choice. Human depletion experiments alter TIA1 isoform production, and TIA1/TIAL1 cooperate with FASTK-dependent splicing regulation. In the cytoplasm, TIAL1 binds AU-rich 3-prime UTRs and suppresses translation of selected mRNAs. Human studies directly demonstrate GADD45A repression and broad repression of translation-factor mRNAs, including functional relief of stress-induced translation inhibition after TIAL1 silencing.

TIAL1 shuttles from a predominantly nuclear steady-state distribution into cytoplasmic stress granules after heat, oxidative, osmotic, or UV stress, where it colocalizes with untranslated polyadenylated RNA. TIAL1 also has a protein-RNA adaptor role in a conserved post-transcriptional mechanism: Drosophila Rox8 recruits miRNA-loaded RISC to yki mRNA, and human TIAR can destabilize YAP mRNA in human cells.

Direct biochemistry also establishes T-rich single-stranded DNA binding, but this is treated as a secondary activity rather than the defining core. The historical cytolytic-granule/nucleolysin literature is retained cautiously: recombinant TIAR fragmented DNA in permeabilized cells and a targeting motif suggested granule localization, but these observations do not establish a broad physiological apoptosis or defense-response role.

The best-supported core picture is therefore a U-rich RNA recognition protein that regulates alternative splicing, AU-rich-3-prime-UTR-dependent translational repression, and stress-responsive mRNP partitioning, with a conserved protein-RNA adaptor activity in miRNA-mediated mRNA control.

Key primary evidence

PMID:8576255: "Mutational analysis indicates that, for both TIA-1 and TIAR, it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs."
PMID:17488725: "TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression"
PMID:9890998: "Here, we report the identification of the RNA-binding protein TIAR as a protein involved in complex 1."
PMID:16600875: "TIAR potently inhibited GADD45alpha translation."
PMID:16537914: "The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression."
PMID:10613902: "TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2alpha to promote the recruitment of untranslated mRNAs to SGs."
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."
PMID:16091628: "TIAR had a nearly 6-fold greater affinity for DNA than RNA"

📚 Additional Documentation

Notes

(TIAL1-notes.md)

TIAL1 review notes

Scope and provenance

Reviewed human TIAL1 (UniProt Q01085; historical protein name TIAR) against all 35 grouped GOA annotations fetched on 2026-07-18.
Reviewed the current UniProtKB/Swiss-Prot record, cached primary papers, the local Reactome record, and current GO term labels.
The configured Falcon deep-research attempt failed with HTTP 402 and the Perplexity-lite fallback failed with HTTP 401. No provider-named deep-research file was created; the manual synthesis is in TIAL1-deep-research-manual.md.

Protein architecture and isoforms

TIAL1 is a 375-aa RNA-binding protein with three N-terminal RNA recognition motifs (RRM1, RRM2, and RRM3) and a glutamine-rich, low-complexity C terminus. UniProt lists two isoforms; isoform 2 inserts 18 residues at canonical position 43 within RRM1. The primary biochemical study found RRM2 necessary and sufficient for specific recognition of uridylate-rich RNA, with RRM1 and RRM3 increasing affinity or supporting other RNA contacts PMID:8576255.

Core RNA activities

Uridine-rich RNA recognition and alternative splicing

TIAR/TIAL1 binds uridine-rich RNA. It regulates alternative pre-mRNA splicing by promoting weak 5-prime splice sites followed by U-rich intronic enhancers PMID:17135269. Depletion in human cells changes the ratio of TIA1 isoforms, providing direct evidence for an endogenous splicing-regulatory role PMID:17488725. Reactome also places TIAL1 among factors contributing to epithelial FGFR2 IIIb splicing, although it notes that its precise role there remains unresolved.

3-prime-UTR binding and translational repression

TIAR binds AU-rich 3-prime UTR elements. The TNF study directly identified TIAR in the cytosolic complex bound to the TNF-alpha AU-rich element PMID:9890998. Direct human-cell experiments showed that TIAR binds the GADD45A 3-prime UTR and inhibits translation PMID:16600875. A broader target study found binding to the 3-prime UTRs of translation-factor mRNAs and strong repression, with TIAR knockdown relieving global UVC-induced translation inhibition PMID:16537914. This supports a new negative-regulation-of-translation annotation.

Stress granules

At steady state TIAL1 is concentrated in the nucleus, but stress causes nuclear-to-cytoplasmic redistribution and colocalization with untranslated poly(A)-positive RNA in stress granules PMID:10613902. The study directly supports stress-granule localization and a role in routing untranslated mRNPs, but its dominant-negative perturbation targeted TIA1 while secondarily trapping endogenous TIAR. Therefore stress-granule assembly is retained as a core biological role in synthesis, while the review avoids overstating a TIAL1-specific single-gene requirement.

Protein-RNA adaptor activity and Hippo/miRNA regulation

The Drosophila Rox8 study showed direct yki 3-prime-UTR binding and recruitment/stabilization of miR-8-loaded RISC. Importantly for the human product, human TIAR promoted yki mRNA degradation in flies and destabilized YAP mRNA in human cells PMID:33203680. The experimental human annotations for protein-RNA adaptor activity, 3-prime-UTR binding, Hippo activation, miRNA silencing, and reduced proliferation are retained, but the downstream pathway and proliferation terms are non-core context-specific consequences.

DNA binding and transcriptional regulation

DNA binding is not merely a domain prediction. Recombinant TIAR bound T-rich single-stranded DNA with higher apparent affinity than the matched RNA and could be displaced by active transcription PMID:16091628. An older alternatively spliced T-cluster-binding product from the same locus bound the PF4 promoter and reduced reporter expression PMID:9207209. DNA binding and transcriptional regulation are therefore retained as experimentally supported but non-core functions; the older TCBP product is not among the two current UniProt isoforms.

Cytolytic-granule, lysosome, defense, and apoptosis boundary

The founding paper identified a lysosome-targeting motif, inferred cytotoxic-granule association, and found that purified recombinant TIAR induced DNA fragmentation in permeabilized target cells PMID:1326761. This supports cytolytic-granule localization as a historical, context-specific observation. Generic lysosome is modified to the more specific cytolytic granule. Defense response and apoptotic process are marked over-annotated because the permeabilized-cell assay and candidate-effector interpretation do not establish a normal, broad physiological role for TIAL1 in either process.

Protein interaction annotations

The three generic protein-binding annotations derive from large-scale DZIP3/MOV10 interaction datasets. The physical associations may be real, but GO protein binding is not informative and does not identify a molecular activity. All three are marked over-annotated; no replacement term is proposed without a demonstrated mechanism for each interaction.

Existing annotation decisions

Group	Decision	Rationale
AU-rich 3-prime-UTR binding IBA	ACCEPT	Direct TNF, GADD45A, and target-mRNA evidence
protein-RNA adaptor IBA/IDA	ACCEPT	Phylogenetic support plus Rox8/TIAR-RISC mechanism
alternative splicing regulation IBA	ACCEPT	Direct human depletion and splice-site studies
nucleic acid binding IEA	MODIFY	Replace with RNA binding; generic parent is uninformative
DNA binding IEA	KEEP_AS_NON_CORE	Direct biochemical DNA binding, secondary to RNA roles
RNA binding and 3-prime-UTR binding	ACCEPT	Multiple direct and high-throughput studies
nucleus/nucleoplasm and cytoplasm/cytosol	ACCEPT	Direct localization and shuttling evidence
cytoplasmic stress granule	ACCEPT	Direct stress-dependent localization
regulation of proliferation IEA	MODIFY	More specific negative regulation is already experimentally supported
cytolytic granule	KEEP_AS_NON_CORE	Historical direct/candidate granule evidence
three protein binding records	MARK_AS_OVER_ANNOTATED	Generic term from interaction screens
negative proliferation, Hippo, miRNA silencing	KEEP_AS_NON_CORE	Supported but pathway/context-specific
defense response	MARK_AS_OVER_ANNOTATED	Candidate CTL effector inference is too broad
lysosome	MODIFY	Cytolytic granule is the supported LRO compartment
Pol II transcription regulation	KEEP_AS_NON_CORE	Direct reporter evidence for older TCBP product
apoptotic process	MARK_AS_OVER_ANNOTATED	Permeabilized-cell DNA fragmentation is insufficient for broad process assignment

Proposed new annotation

GO:0017148 negative regulation of translation, supported by direct TIAR target binding, reporter/translation measurements, and relief after TIAL1 silencing in human cells PMID:16537914

Open issues

Determine whether the RRM1 insertion in isoform 2 alters DNA recognition, RNA target choice, nucleocytoplasmic shuttling, or condensation.
Test whether the old TCBP transcript/protein is still produced from the human TIAL1 locus and how it relates to current transcript models.
Resolve the TIAL1-specific contribution to stress-granule assembly separately from the partly redundant TIA1 and G3BP proteins.
Reassess endogenous cytolytic-granule localization and physiological CTL effector function with modern isoform-specific reagents.

📄 View Raw YAML

id: Q01085
gene_symbol: TIAL1
product_type: PROTEIN
aliases:
- TIAR
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q01085-1
- name: '2'
  id: Q01085-2
  sequence_note: VSP_043700
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: >-
    Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied
    by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10613902
  title: RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules.
  findings:
  - statement: TIA-1 and TIAR recruit untranslated mRNAs to mammalian stress granules downstream of stress-induced eIF2-alpha phosphorylation.
    supporting_text: TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2α to promote the recruitment of untranslated mRNAs to SGs.
    reference_section_type: INTRODUCTION
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. This is the decisive
      direct human-cell localization and stress-granule study, although its
      dominant-negative construct targets TIA1 while trapping endogenous TIAR.
- id: PMID:1326761
  title: Identification and functional characterization of a TIA-1-related nucleolysin.
  full_text_unavailable: true
  findings:
  - statement: Recombinant TIAR induces DNA fragmentation in permeabilized target cells.
    supporting_text: Like TIA-1, purified recombinant TIAR induced DNA fragmentation in permeabilized target cells.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: A lysosome-targeting motif led the authors to propose cytotoxic-granule association.
    supporting_text: The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The biochemical DNA-
      fragmentation result and candidate granule localization are real, but
      neither establishes a broad physiological apoptosis or defense role.
- id: PMID:8576255
  title: Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities.
  full_text_unavailable: true
  findings:
  - statement: RRM2 mediates sequence-specific binding to uridylate-rich RNA.
    supporting_text: it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. This is the foundational direct
      biochemical analysis of TIAR RNA specificity and RRM contributions.
- id: PMID:9207209
  title: An alternative form of nucleolysin binds to a T-cluster DNA in the silencer element of platelet factor 4 gene.
  full_text_unavailable: true
  findings:
  - statement: The alternative T-cluster-binding product binds the PF4 promoter and represses its reporter activity.
    supporting_text: Co-transfection experiments showed that TCBP reduced the gene expression from the PF4 promoter.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The reported product maps to
      the nucleolysin/TIAL1 locus, but it is not among the two current UniProt
      isoforms, so the transcription phenotype is treated as non-core.
- id: PMID:9890998
  title: Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA.
  full_text_unavailable: true
  findings:
  - statement: TIAR is a component of the cytosolic protein complex bound to the TNF-alpha AU-rich element.
    supporting_text: Here, we report the identification of the RNA-binding protein TIAR as a protein involved in complex 1.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. This directly supports
      AU-rich 3-prime-UTR binding by TIAR.
- id: PMID:16091628
  title: Novel DNA-binding properties of the RNA-binding protein TIAR.
  findings:
  - statement: Recombinant TIAR binds T-rich single-stranded DNA with higher apparent affinity than the corresponding RNA.
    supporting_text: TIAR had a nearly 6-fold greater affinity for DNA than RNA
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. This direct biochemical
      study verifies DNA binding but does not establish it as the dominant
      physiological activity.
- id: PMID:16537914
  title: Translational repression by RNA-binding protein TIAR.
  full_text_unavailable: true
  findings:
  - statement: TIAR binds 3-prime UTRs of translation-factor mRNAs and represses their translation.
    supporting_text: TIAR bound the 3'-untranslated regions of these mRNAs and potently suppressed their translation
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: TIAR silencing relieves UVC-induced global translation inhibition.
    supporting_text: The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. Direct target-binding,
      translation, and silencing experiments establish negative regulation of
      translation in human cells.
- id: PMID:16600875
  title: Posttranscriptional derepression of GADD45alpha by genotoxic stress.
  full_text_unavailable: true
  findings:
  - statement: TIAR binds the GADD45A 3-prime UTR and directly represses translation.
    supporting_text: TIAR potently inhibited GADD45alpha translation.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. This provides a direct
      transcript-specific example of human TIAR translational repression.
- id: PMID:17135269
  title: Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.
  full_text_unavailable: true
  findings:
  - statement: TIA1 and TIAR promote suboptimal 5-prime splice sites followed by U-rich intronic enhancers.
    supporting_text: TIA-1 (T-cell intracellular antigen 1) and TIAR (TIA-1-related) proteins regulate alternative pre-mRNA splicing by promoting the use of suboptimal 5' splice sites followed by uridine-rich intronic enhancer sequences.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The joint depletion and Fas
      reporter experiments directly support a TIAL1 splicing-regulatory role.
- id: PMID:17488725
  title: Two isoforms of the T-cell intracellular antigen 1 (TIA-1) splicing factor display distinct splicing regulation activities. Control of TIA-1 isoform ratio by TIA-1-related protein.
  full_text_unavailable: true
  findings:
  - statement: TIAR depletion changes endogenous TIA1 alternative isoform output in human and mouse cells.
    supporting_text: TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. Human depletion provides direct
      endogenous evidence for alternative-splicing regulation by TIAL1.
- id: PMID:20932473
  title: DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.
  findings:
  - statement: DNA damage promotes p38-dependent phosphorylation and release of TIAR from GADD45A mRNA.
    supporting_text: we did observe strong direct phosphorylation of TIAR by p38 in vitro
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. This defines a
      stress-regulated TIAR-GADD45A post-transcriptional switch.
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  full_text_unavailable: true
  findings:
  - statement: Interactome capture identified a biochemically defined mammalian mRNA-bound proteome.
    supporting_text: We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The GOA HDA records TIAL1 in
      the human mRNA-interactome dataset; the study is broad, not
      TIAL1-mechanistic.
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  full_text_unavailable: true
  findings:
  - statement: UV crosslinking and oligo-dT purification identified the mRNA-bound proteome of a human cell line.
    supporting_text: Application to a human embryonic kidney cell line identified close to 800 proteins.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The GOA HDA records TIAL1 in
      the source dataset and independently supports direct mRNA association.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings:
  - statement: BioPlex 2.0 produced a large candidate human protein co-association network.
    supporting_text: With more than 56,000 candidate interactions
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. The GOA IPI records a
      DZIP3-TIAL1 co-association from the screen, but generic protein binding is
      not an informative molecular activity.
- id: PMID:33203680
  title: Rox8 promotes microRNA-dependent yki messenger RNA decay.
  full_text_unavailable: true
  findings:
  - statement: Human TIAR can promote yki degradation in flies and destabilize YAP mRNA in human cells.
    supporting_text: 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.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract were checked. The paper directly tests human
      TIAR, while the detailed RISC-recruitment genetics are in Drosophila.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: BioPlex 3.0 generated cell-line-specific human protein co-association networks.
    supporting_text: These networks model the interactome whose structure encodes protein function, localization, and complex membership.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. The GOA IPI records a
      DZIP3-TIAL1 co-association, but it does not justify a generic protein-
      binding function term.
- id: PMID:34517762
  title: MOV10 Helicase Interacts with Coronavirus Nucleocapsid Protein and Has Antiviral Activity.
  findings:
  - statement: Endogenous MOV10 and TIAR co-immunoprecipitate even in uninfected human cells.
    supporting_text: An interaction between endogenous MOV10 and the SG component TIAR was also identified, even in mock-infected cells.
    reference_section_type: DISCUSSION
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC identity and full text were checked. The endogenous
      co-immunoprecipitation supports association, but not a specific molecular
      activity for TIAL1.
- id: Reactome:R-HSA-6803527
  title: ESRP1 and 2 bind FGFR2 pre-mRNA to promote FGFR2b maturation and expression
  findings:
  - statement: Reactome includes TIAL1 among nucleoplasmic factors contributing to FGFR2 IIIb-specific splicing.
    supporting_text: Other factors that appear to contribute to IIIb-specific splicing include hnRNPM, TIA1 and TIAL1
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      The cached Reactome record was checked. It supports nucleoplasmic
      localization and pathway context while explicitly noting that the precise
      TIAL1 role remains to be elucidated.
- id: file:human/TIAL1/TIAL1-uniprot.txt
  title: UniProtKB record for human TIAL1 (Q01085)
  findings:
  - statement: TIAL1 is a reviewed 375-amino-acid protein.
    supporting_text: Reviewed;         375 AA.
  - statement: UniProt assigns three RNA recognition motifs.
    supporting_text: FT   DOMAIN          9..85
  - statement: UniProt records nuclear, cytoplasmic, cytolytic-granule, and stress-granule localization.
    supporting_text: Cytoplasm, Stress granule
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      The current reviewed UniProt record was checked directly for sequence,
      domains, isoforms, localization, and primary-literature provenance.
- id: file:human/TIAL1/TIAL1-notes.md
  title: Manual literature and annotation review notes for human TIAL1
  findings:
  - statement: All 35 grouped GOA annotations were manually adjudicated.
    supporting_text: '## Existing annotation decisions'
  - statement: The notes distinguish core RNA functions from historical candidate nucleolysin claims.
    supporting_text: '## Cytolytic-granule, lysosome, defense, and apoptosis boundary'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Manual synthesis of reviewed UniProt, GOA, cached primary literature,
      Reactome, and verified GO term labels.
- id: file:human/TIAL1/TIAL1-deep-research-manual.md
  title: Manual literature synthesis for human TIAL1 (Q01085)
  findings:
  - statement: The best-supported core is U-rich RNA recognition coupled to splicing, translation control, and stress-responsive mRNP partitioning.
    supporting_text: The best-supported core picture is therefore a U-rich RNA recognition protein
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Manual research was required because both configured automated providers
      failed; conclusions are anchored to reviewed records and primary sources.
existing_annotations:
- term:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic inference assigns specific binding to AU-rich regions in
      mRNA 3-prime UTRs.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:9890998
    - PMID:16600875
    - file:human/TIAL1/TIAL1-deep-research-manual.md
    supported_by:
    - reference_id: PMID:9890998
      supporting_text: Here, we report the identification of the RNA-binding protein TIAR as a protein involved in complex 1.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
    - reference_id: file:human/TIAL1/TIAL1-deep-research-manual.md
      supporting_text: The best-supported core picture is therefore a U-rich RNA recognition protein
- term:
    id: GO:0140517
    label: protein-RNA adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic inference assigns an ancestral protein-RNA adaptor activity.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:33203680
    supported_by:
    - reference_id: PMID:33203680
      supporting_text: 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.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference assigns regulation of spliceosomal alternative
      splicing.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:17135269
    - PMID:17488725
    supported_by:
    - reference_id: PMID:17488725
      supporting_text: TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro maps the RRM architecture to the generic nucleic-acid-binding
      parent term.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0003723
      label: RNA binding
    additional_reference_ids:
    - PMID:8576255
    supported_by:
    - reference_id: PMID:8576255
      supporting_text: it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro propagates DNA binding from the TIAR RRM2 family signature.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:16091628
    supported_by:
    - reference_id: PMID:16091628
      supporting_text: TIAR had a nearly 6-fold greater affinity for DNA than RNA
      reference_section_type: ABSTRACT
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro assigns RNA binding from the three-RRM architecture.
    action: ACCEPT
    reason: >-
      RNA binding is the fundamental molecular activity of TIAL1 and is
      established by direct biochemical specificity measurements and multiple
      human mRNA-interactome datasets.
    additional_reference_ids:
    - PMID:8576255
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA predicts binding to mRNA 3-prime UTRs.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:16537914
    - PMID:16600875
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated annotation places TIAL1 in the nucleus.
    action: ACCEPT
    reason: >-
      Direct human-cell imaging shows that TIA1 and TIAR are concentrated in
      the nucleus at steady state, consistent with their nuclear splicing role.
    additional_reference_ids:
    - PMID:10613902
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated annotation places TIAL1 in the cytoplasm.
    action: ACCEPT
    reason: >-
      TIAL1 shuttles into the cytoplasm and directly accumulates there during
      stress, where it binds 3-prime UTRs, represses translation, and enters
      stress granules.
    additional_reference_ids:
    - PMID:10613902
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt location mapping places TIAL1 in cytoplasmic stress granules.
    action: ACCEPT
    reason: >-
      Direct human-cell microscopy shows stress-dependent colocalization of
      TIA1/TIAR with polyadenylated untranslated RNA in cytoplasmic stress
      granules.
    additional_reference_ids:
    - PMID:10613902
    supported_by:
    - reference_id: PMID:10613902
      supporting_text: TIA-1 and TIAR colocalize with poly(A)(+) RNA at cytoplasmic foci that resemble the stress granules
      reference_section_type: ABSTRACT
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA predicts a broad role in regulation of cell proliferation.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0008285
      label: negative regulation of cell population proliferation
    additional_reference_ids:
    - PMID:33203680
- term:
    id: GO:0044194
    label: cytolytic granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt maps the historical TIAR location statement to cytolytic granule.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:1326761
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: BioPlex reports a candidate TIAL1-DZIP3 co-association.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex 3.0 reports a candidate TIAL1-DZIP3 co-association.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34517762
  qualifier: enables
  review:
    summary: Endogenous TIAR and MOV10 co-immunoprecipitate in human cells.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:34517762
      supporting_text: An interaction between endogenous MOV10 and the SG component TIAR was also identified, even in mock-infected cells.
      reference_section_type: DISCUSSION
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Human Protein Atlas immunofluorescence detects TIAL1 in nucleoplasm.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Human Protein Atlas immunofluorescence detects TIAL1 in cytosol.
    action: ACCEPT
    reason: >-
      Cytosolic localization is consistent with direct 3-prime-UTR translation
      regulation and stress-dependent recruitment to cytoplasmic granules.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:10613902
  qualifier: located_in
  review:
    summary: Direct human-cell experiments place TIAR predominantly in the nucleus at steady state.
    action: ACCEPT
    reason: >-
      The paper distinguishes TIAR from TIA1 with specific antibodies and shows
      nuclear concentration before stress-induced redistribution.
    supported_by:
    - reference_id: PMID:10613902
      supporting_text: TIA-1 and TIAR are concentrated in the nuclei of the DU145 human prostate cell line
      reference_section_type: RESULTS
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator-reviewed transfer from mouse Tial1 assigns cytoplasmic localization.
    action: ACCEPT
    reason: >-
      The orthology transfer is sound and independently corroborated by direct
      human-cell studies showing cytoplasmic redistribution of TIAR under
      stress.
    additional_reference_ids:
    - PMID:10613902
- term:
    id: GO:0044194
    label: cytolytic granule
  evidence_type: EXP
  original_reference_id: PMID:1326761
  qualifier: located_in
  review:
    summary: The founding study proposed TIAR as a cytotoxic-granule-associated nucleolysin.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:1326761
      supporting_text: The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0140517
    label: protein-RNA adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:33203680
  qualifier: enables
  review:
    summary: Human TIAR functionally substitutes for Rox8 in a target-RNA/RISC regulatory mechanism.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:33203680
      supporting_text: Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:33203680
  qualifier: enables
  review:
    summary: The Rox8/TIAR study assigns direct 3-prime-UTR binding.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:9890998
    - PMID:16537914
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:33203680
  qualifier: involved_in
  review:
    summary: Rox8/TIAR activity suppresses Hippo-dependent tissue overgrowth.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0035332
    label: positive regulation of hippo signaling
  evidence_type: IMP
  original_reference_id: PMID:33203680
  qualifier: involved_in
  review:
    summary: Rox8/TIAR-mediated yki/YAP mRNA destabilization increases Hippo-pathway output.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:2000637
    label: positive regulation of miRNA-mediated gene silencing
  evidence_type: IGI
  original_reference_id: PMID:33203680
  qualifier: involved_in
  review:
    summary: Rox8 stabilizes miR-8-loaded RISC targeting of yki mRNA, and human TIAR functionally complements this mechanism.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:33203680
      supporting_text: recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6803527
  qualifier: located_in
  review:
    summary: Reactome places TIAL1 in the nucleoplasmic FGFR2 alternative-splicing reaction context.
    action: ACCEPT
    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.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: UV-crosslinking interactome capture identifies TIAL1 in the human mRNA-bound proteome.
    action: ACCEPT
    reason: >-
      The high-throughput direct RNA-association evidence independently
      confirms the well-established RRM-mediated RNA-binding activity.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: An independent UV-crosslinking/oligo-dT proteome study identifies TIAL1 as mRNA bound.
    action: ACCEPT
    reason: >-
      This independent high-throughput dataset corroborates direct mRNA binding,
      which is already supported by targeted biochemical studies.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator-reviewed transfer from mouse Tial1 assigns nuclear localization.
    action: ACCEPT
    reason: >-
      The transfer is consistent with direct human-cell imaging and the
      conserved nuclear alternative-splicing role.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator-reviewed orthology transfer assigns stress-granule localization.
    action: ACCEPT
    reason: >-
      The transfer is independently corroborated by direct human-cell
      microscopy showing stress-dependent TIAR accumulation with untranslated
      polyadenylated RNA.
    additional_reference_ids:
    - PMID:10613902
- term:
    id: GO:0006952
    label: defense response
  evidence_type: TAS
  original_reference_id: PMID:1326761
  qualifier: involved_in
  review:
    summary: The founding paper proposed TIAR as a candidate cytotoxic-lymphocyte nucleolysin.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:1326761
      supporting_text: Our data suggest that the granules of CTLs contain at least two candidate nucleolysins involved in CTL killing.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: TAS
  original_reference_id: PMID:1326761
  qualifier: enables
  review:
    summary: The founding sequence study identifies three RNA-binding domains in TIAR.
    action: ACCEPT
    reason: >-
      RNA binding is strongly corroborated by later direct biochemical studies
      that define uridylate specificity and the dominant role of RRM2.
    additional_reference_ids:
    - PMID:8576255
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: TAS
  original_reference_id: PMID:1326761
  qualifier: located_in
  review:
    summary: A lysosome-targeting motif was used to infer granule localization.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0044194
      label: cytolytic granule
    supported_by:
    - reference_id: PMID:1326761
      supporting_text: The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TIAR is probably a cytotoxic granule-associated protein.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:9207209
  qualifier: involved_in
  review:
    summary: An alternative T-cluster-binding product represses a PF4 promoter reporter.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:16091628
    supported_by:
    - reference_id: PMID:9207209
      supporting_text: Co-transfection experiments showed that TCBP reduced the gene expression from the PF4 promoter.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:1326761
  qualifier: involved_in
  review:
    summary: Recombinant TIAR induces DNA fragmentation in permeabilized target cells.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:1326761
      supporting_text: Like TIA-1, purified recombinant TIAR induced DNA fragmentation in permeabilized target cells.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IMP
  original_reference_id: PMID:16537914
  qualifier: involved_in
  review:
    summary: TIAL1 silencing relieves stress-induced global translation inhibition in human cells.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:16537914
      supporting_text: The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression.
      reference_section_type: ABSTRACT
      full_text_unavailable: true
- term:
    id: GO:0034063
    label: stress granule assembly
  evidence_type: IDA
  original_reference_id: PMID:10613902
  qualifier: involved_in
  review:
    summary: TIA1 and TIAR recruit untranslated mRNAs into mammalian stress granules.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:10613902
      supporting_text: TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2α to promote the recruitment of untranslated mRNAs to SGs.
      reference_section_type: INTRODUCTION
core_functions:
- description: >-
    TIAL1 recognizes U-rich pre-mRNA elements through its RRM domains and
    promotes alternative splice-site choice at weak 5-prime splice sites in the
    nucleoplasm.
  molecular_function:
    id: GO:0003723
    label: RNA binding
  directly_involved_in:
  - id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  locations:
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: PMID:17488725
    supporting_text: TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- description: >-
    Cytosolic TIAL1 binds AU-rich and other regulatory elements in selected mRNA
    3-prime UTRs and represses their translation, including GADD45A and mRNAs
    encoding translation factors.
  molecular_function:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  directly_involved_in:
  - id: GO:0017148
    label: negative regulation of translation
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16537914
    supporting_text: TIAR bound the 3'-untranslated regions of these mRNAs and potently suppressed their translation
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- description: >-
    During environmental stress, TIAL1 relocalizes with untranslated
    polyadenylated mRNPs into cytoplasmic stress granules and participates in
    stress-granule assembly.
  molecular_function:
    id: GO:0003723
    label: RNA binding
  directly_involved_in:
  - id: GO:0034063
    label: stress granule assembly
  locations:
  - id: GO:0010494
    label: cytoplasmic stress granule
  supported_by:
  - reference_id: PMID:10613902
    supporting_text: TIA-1 and TIAR act downstream of the stress-induced phosphorylation of eIF-2α to promote the recruitment of untranslated mRNAs to SGs.
    reference_section_type: INTRODUCTION
proposed_new_terms: []
knowledge_gaps:
- gap_statement: >-
    The two current human TIAL1 isoforms have not been functionally resolved,
    particularly the effect of the isoform-2 insertion within RRM1.
  boundary: >-
    UniProt defines the sequence difference, but the primary splicing,
    translation, DNA-binding, and stress-granule studies generally do not
    distinguish endogenous TIAL1 isoforms.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: >-
    Isoform resolution is needed to know whether RRM1 sequence variation changes
    RNA/DNA specificity, target selection, localization, or condensation.
  resolution: >-
    Combine isoform-resolved long-read expression and eCLIP with matched
    isoform rescue after endogenous TIAL1 depletion.
  provenance:
  - reference_id: file:human/TIAL1/TIAL1-notes.md
    supporting_text: isoform 2 inserts 18 residues at canonical position 43 within RRM1
- gap_statement: >-
    TIAL1's independent requirement for stress-granule assembly is unresolved
    because TIA1 and G3BP-family proteins provide partly redundant nucleation
    activities.
  boundary: >-
    Direct studies establish recruitment and participation, but the classic
    dominant-negative construct targets TIA1 and secondarily traps endogenous
    TIAR.
  gap_kind:
  - BIOLOGY
  dark_aspect: BP_DARK
  status: OPEN
  significance: >-
    Separating recruitment from essential nucleation will clarify whether TIAL1
    is a core scaffold or a condition-dependent contributor.
  resolution: >-
    Use acute single and combinatorial TIAL1, TIA1, G3BP1, and G3BP2 depletion
    with endogenous live-cell stress-granule imaging and separation-of-function
    rescue.
  provenance:
  - reference_id: file:human/TIAL1/TIAL1-notes.md
    supporting_text: its dominant-negative perturbation targeted TIA1 while secondarily trapping endogenous TIAR
- gap_statement: >-
    The physiological relevance of cytolytic-granule localization and
    nucleolytic activity remains uncertain.
  boundary: >-
    The founding study used a targeting motif, fractionation context, and
    recombinant protein in permeabilized cells; modern endogenous,
    isoform-specific evidence is lacking.
  gap_kind:
  - BIOLOGY
  dark_aspect: CC_DARK
  status: OPEN
  significance: >-
    Resolving this issue would distinguish a specialized immune effector role
    from an historical overinterpretation of biochemical activity.
  resolution: >-
    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:
  - reference_id: file:human/TIAL1/TIAL1-notes.md
    supporting_text: Generic lysosome is modified to the more specific cytolytic granule.
suggested_questions:
- question: >-
    Does the RRM1 insertion in TIAL1 isoform 2 alter RNA target choice, DNA
    binding, nucleocytoplasmic shuttling, or stress-granule condensation?
- question: >-
    How broadly does human TIAL1 recruit miRNA/RISC machinery beyond the
    demonstrated YAP/yki context?
- question: >-
    Is TIAL1 independently required for particular classes of stress granules,
    or is it functionally redundant with TIA1 and G3BP proteins?
- question: >-
    Is the historical TCBP product expressed from the modern TIAL1 locus, and
    does TIAL1 regulate transcription through DNA binding in vivo?
- question: >-
    Does endogenous TIAL1 enter cytolytic granules and contribute directly to
    cytotoxic-lymphocyte target killing?
suggested_experiments:
- 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.
  description: >-
    Perform isoform-resolved eCLIP, quantitative DNA/RNA binding, and matched
    rescue of splicing and translation reporters after endogenous TIAL1
    depletion.
  experiment_type: Isoform-resolved target mapping and functional rescue
- hypothesis: >-
    TIAL1 is conditionally required for assembly of specific stress-granule
    subclasses when TIA1/G3BP nucleation capacity is limiting.
  description: >-
    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.
  experiment_type: Genetic epistasis and live-cell condensate analysis
- hypothesis: >-
    Human TIAL1 recruits RISC to a defined subset of 3-prime-UTR targets in
    addition to YAP.
  description: >-
    Combine AGO2/TIAL1 co-immunoprecipitation, eCLIP, miRNA perturbation, and
    target 3-prime-UTR reporters with TIAL1 wild-type and adaptor-defective
    rescue.
  experiment_type: RNP mapping and reporter epistasis
- hypothesis: >-
    DNA binding positions TIAL1 near nascent U-rich transcripts rather than
    serving as a general transcription-factor activity.
  description: >-
    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.
  experiment_type: Chromatin-RNA coupling analysis
- hypothesis: >-
    Cytolytic-granule localization and target-cell nucleolytic activity are
    specialized endogenous TIAL1 functions in human cytotoxic lymphocytes.
  description: >-
    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.
  experiment_type: Endogenous localization and immune-cell functional rescue

TIAL1

Gene Description

Existing Annotations Review

Core Functions

TIAL1 recognizes U-rich pre-mRNA elements through its RRM domains and promotes alternative splice-site choice at weak 5-prime splice sites in the nucleoplasm.

Cytosolic TIAL1 binds AU-rich and other regulatory elements in selected mRNA 3-prime UTRs and represses their translation, including GADD45A and mRNAs encoding translation factors.

During environmental stress, TIAL1 relocalizes with untranslated polyadenylated mRNPs into cytoplasmic stress granules and participates in stress-granule assembly.

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Deep Research

Manual

Manual literature synthesis for human TIAL1 (Q01085)

Research status

Synthesis

Key primary evidence

📚 Additional Documentation

Notes

TIAL1 review notes

Scope and provenance

Protein architecture and isoforms

Core RNA activities

Uridine-rich RNA recognition and alternative splicing

3-prime-UTR binding and translational repression

Stress granules

Protein-RNA adaptor activity and Hippo/miRNA regulation

DNA binding and transcriptional regulation

Cytolytic-granule, lysosome, defense, and apoptosis boundary

Protein interaction annotations

Existing annotation decisions

Proposed new annotation

Open issues

📄 View Raw YAML