{"gene":"TRIOBP","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"TRIOBP-1/Tara directly binds F-actin in vitro and associates with the Trio guanine nucleotide exchange factor (via yeast two-hybrid and mammalian co-immunoprecipitation). Overexpression of Tara stabilizes F-actin structures, enhances stress fibers and cortical actin, and increases cell spreading, while Tara-expressing cells show relative resistance to Latrunculin B-induced F-actin destabilization.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro F-actin binding assay, Latrunculin B treatment, fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus direct in vitro binding assay plus functional cellular phenotype; foundational paper replicated by subsequent studies","pmids":["11148140"],"is_preprint":false},{"year":2005,"finding":"Mutations in a novel long isoform of TRIOBP (218 kDa) cause DFNB28 hereditary deafness. The long isoform has a restricted expression profile including cochlea, retina, and fetal brain. Antibody staining shows TRIOBP protein expression in sensory cells of the inner ear and colocalization with F-actin along the length of stereocilia.","method":"Genetic linkage/mutation analysis, RT-PCR expression profiling, immunofluorescence with anti-TRIOBP antibody","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunolocalization to stereocilia F-actin, genetic mapping, but localization not coupled to functional rescue experiment","pmids":["16385458"],"is_preprint":false},{"year":2005,"finding":"Six distinct TRIOBP mutant alleles (four nonsense, two frameshift) in exon 6 cosegregate with autosomal recessive nonsyndromic deafness across seven families, establishing TRIOBP as the DFNB28 gene.","method":"Genetic linkage analysis, mutation screening, cosegregation analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic cosegregation in multiple families; no direct molecular mechanism experiment","pmids":["16385457"],"is_preprint":false},{"year":2008,"finding":"HECTD3, a HECT-domain E3 ubiquitin ligase, directly binds TRIOBP-1/Tara in vitro and forms a complex in vivo. HECTD3 overexpression enhances ubiquitination of Tara and promotes its degradation; siRNA depletion of HECTD3 decreases Tara degradation. HECTD3 depletion also leads to multipolar spindle formation, suggesting that HECTD3-mediated ubiquitination and degradation of Tara facilitates cell cycle progression.","method":"In vitro pull-down, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, confocal microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed in vitro and in vivo, functional ubiquitination assay with gain- and loss-of-function, single lab","pmids":["18194665"],"is_preprint":false},{"year":2010,"finding":"TRIOBP isoform 4 (TRIOBP-4) bundles actin filaments into uniquely dense bundles in vitro resembling stereocilia rootlets. TRIOBP localizes specifically to rootlets of inner ear hair cell stereocilia. Triobp-knockout mice (Triobp(Δex8/Δex8)) are profoundly deaf; their stereocilia develop normally but fail to form rootlets and are easier to deflect and damage. Thus TRIOBP F-actin bundling provides mechanical durability and rigidity to stereocilia.","method":"In vitro F-actin bundling assay with purified TRIOBP-4, immunolocalization, knockout mouse model with auditory and electrophysiology testing, electron microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of actin bundling with purified protein, confirmed by knockout mouse phenotype with direct structural and functional measurements; replicated by subsequent work","pmids":["20510926"],"is_preprint":false},{"year":2011,"finding":"Tara is enriched at E-cadherin-based adherens junctions. Tara knockdown in MDCK cells activates Rac1 through the Trio RhoGEF (which binds E-cadherin), leading to increased p38 phosphorylation and phosphorylation of Tbx3, a transcriptional E-cadherin repressor, thereby decreasing E-cadherin transcription. E-cadherin loss is rescued by ITX3 (Trio RhoGEF inhibitor), SB203580 (p38 inhibitor), or dephosphomimetic Tbx3. Tara also modulates circumferential actin-belt density and epithelial cyst morphology.","method":"shRNA knockdown, co-immunoprecipitation, pharmacological inhibition, phosphomimetic/dephosphomimetic mutant rescue, confocal microscopy, luciferase reporter","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, pharmacological rescue, mutant rescue, Co-IP) in a single rigorous study establishing pathway placement","pmids":["21482718"],"is_preprint":false},{"year":2012,"finding":"Polo-like kinase 1 (Plk1) interacts with and phosphorylates Tara at Thr-457 in vivo and in vitro. This Plk1-dependent phosphorylation is required for centrosomal localization of Tara. A non-phosphorylatable Tara mutant (T457A) causes aberrant mitotic delay in HeLa cells, demonstrating that Plk1-mediated phosphorylation of Tara at Thr-457 is required for faithful chromosome segregation.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphosite mutagenesis, confocal microscopy, cell cycle analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in vivo phosphorylation site mutagenesis with functional readout; single lab but multiple orthogonal methods","pmids":["22820163"],"is_preprint":false},{"year":2013,"finding":"The R1 repeat motif is the major actin-binding domain of TRIOBP-4. Deletion of both R1 and R2 motifs completely abolishes actin-binding and bundling activities and impairs localization to cellular actin structures. Deletion of R2 alone retains F-actin bundling and actin colocalization. R1-deleted TRIOBP-4 (consisting mainly of R2) forms only thin F-actin bundles in vitro and fails to colocalize with actin filaments in cells.","method":"Actin cosedimentation assay, in vitro F-actin bundling assay, electron microscopy, fluorescence microscopy, deletion mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with deletion mutants, multiple orthogonal structural and cellular readouts, single lab","pmids":["23789641"],"is_preprint":false},{"year":2014,"finding":"TAP68 (TRIOBP-1) interacts with TRF1 in mitotic cells. TAP68 co-localizes with TRF1 to telomeres during interphase. After nuclear envelope breakdown, TAP68 translocates to spindle poles and recruits TRF1. Nek2A-dependent phosphorylation of TAP68 at Thr-221 coincides with its dissociation from telomeres. The first coiled-coil domain of TAP68 is responsible for binding and recruiting TRF1 and tankyrase 1 to the centrosome. siRNA depletion of TAP68 blocks centrosomal localization of TRF1 and tankyrase 1 and perturbs chromosome segregation.","method":"Co-immunoprecipitation, siRNA knockdown, domain deletion mapping, immunofluorescence microscopy, live cell imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, siRNA phenotype with multiple orthogonal methods; single lab","pmids":["24692559"],"is_preprint":false},{"year":2014,"finding":"TRIOBP-4 and TRIOBP-5 are upregulated in pancreatic carcinoma cells. Knockdown of TRIOBP-4/-5 leads to loss of filopodia and decreased cell motility; re-expression of GFP-TRIOBP-4 or -5 restores filopodial formation in TRIOBP-4/-5-deficient PANC-1 cells, demonstrating a role in promoting cell motility via regulation of filopodia actin structures.","method":"siRNA knockdown, GFP-tagged rescue expression, confocal microscopy, wound healing/motility assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phenotype and rescue experiment; single lab","pmids":["25130170"],"is_preprint":false},{"year":2014,"finding":"TRIOBP-1 has a high aggregation propensity when over-expressed in neuroblastoma cells, whereas the TRIOBP-4 isoform does not. Endogenous TRIOBP-1 can spontaneously aggregate, doing so more in post-mitotic cell cultures. Aggregated TRIOBP-1 affects cell morphology in Neuroscreen-1 cells.","method":"Over-expression in neuroblastoma/NS-1 cells, insolubility assay, immunofluorescence microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cellular aggregation assay with isoform comparison and morphological readout; single lab","pmids":["25333879"],"is_preprint":false},{"year":2016,"finding":"Ndel1 interacts physically with Tara (TRIOBP-1). Ndel1- or Tara-deficient cells are defective in cell migration. Tara overexpression accumulates Ndel1 at the cell periphery, co-localizing with F-actin; this redistribution requires the Ndel1-interacting domain of Tara. Co-expression of Ndel1 and Tara causes synergistic increases in F-actin levels and filopodia formation, indicating that the Ndel1-Tara complex regulates actin remodeling during cell movement.","method":"Co-immunoprecipitation, domain deletion analysis, wound healing assay, Boyden chamber assay, confocal microscopy, siRNA knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional experiments with domain deletion and migration assays; single lab, single study","pmids":["27546710"],"is_preprint":false},{"year":2017,"finding":"TRIOBP-1 possesses two distinct coiled-coil domains (central and C-terminal). The central domain inhibits F-actin depolymerization, mediates oligomerization of TRIOBP-1, and affects neurite outgrowth along with the N-terminal PH domain. The aggregation propensity of TRIOBP-1 arises from its central domain, with an 8-25 amino acid linker region (around residues 324-348) between the first two coiled coils being essential for aggregate formation.","method":"Domain deletion mutagenesis, F-actin depolymerization assay, insolubility assay in neuroblastoma cells, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mapping with multiple functional readouts; single lab","pmids":["28438837"],"is_preprint":false},{"year":2018,"finding":"TRIOBP-1 interacts directly with the hERG cardiac potassium channel protein (identified by yeast two-hybrid and confirmed by FRET and co-immunoprecipitation in HEK293 cells and native cardiac tissue). TRIOBP-1 overexpression reduces hERG surface expression and current density (IKr); shRNA knockdown of TRIOBP-1 increases hERG protein levels. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression causes intracellular co-sequestration of hERG, reduces native IKr, and disrupts action potential repolarization.","method":"Yeast two-hybrid, FRET, co-immunoprecipitation, shRNA knockdown, whole-cell patch clamp, immunolabeling, human iPSC-derived cardiomyocytes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction confirmed by three orthogonal methods (Y2H, FRET, Co-IP) in multiple cell systems including native tissue; functional readout via electrophysiology","pmids":["29507111"],"is_preprint":false},{"year":2018,"finding":"Sp1 transcriptionally suppresses miR-3178, and miR-3178 directly targets the 3' UTR of TRIOBP-1 and TRIOBP-5, reducing their expression. Overexpression of TRIOBP-1 rescues the inhibitory effect of miR-3178 on cell migration and invasion, establishing TRIOBP-1 as a downstream effector of the Sp1/miR-3178 axis in cancer cell metastasis.","method":"Luciferase reporter assay (3'UTR), ChIP, migration/invasion assays, overexpression rescue","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR luciferase validates direct miRNA targeting, rescue experiment confirms TRIOBP as effector; single lab","pmids":["30195749"],"is_preprint":false},{"year":2022,"finding":"ANKRD24 concentrates at the stereocilia insertion point forming a ring at the junction between lower and upper rootlets, where it surrounds and binds TRIOBP-5 which bundles rootlet F-actin. TRIOBP-5 is mislocalized in Ankrd24KO/KO hair cells, and ANKRD24 no longer localizes with rootlets in mice lacking TRIOBP-5; exogenous DsRed-TRIOBP-5 restores endogenous ANKRD24 to rootlets, demonstrating mutual interdependence. Ankrd24KO/KO mice show progressive hearing loss and increased susceptibility to overstimulation.","method":"Super-resolution microscopy, knockout mouse models, exogenous rescue expression, immunolocalization, auditory function testing","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — super-resolution localization, reciprocal knockout mislocalization phenotypes, and exogenous rescue; multiple orthogonal methods","pmids":["35175278"],"is_preprint":false},{"year":2022,"finding":"TRIOBP deficiency (knockout of isoforms 4 and 5 or isoform 5 alone) significantly disrupts the magnitude and orientation of bidirectional radial stiffness gradients in the cochlear sensory epithelium and causes ultrastructural changes in supporting cell phalangeal microfilaments and hair cell cuticular plate F-actin bundles, as measured by nanoscale AFM mapping.","method":"Atomic force microscopy (AFM) stiffness mapping, focused ion beam/scanning electron microscopy, Triobp knockout mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct nanomechanical measurement with sub-100-nm resolution in multiple knockout mouse models; single study with multiple orthogonal structural methods","pmids":["35737845"],"is_preprint":false},{"year":2022,"finding":"TRIOBP-1 aggregation in neuroblastoma cells can be narrowed to an 8 amino acid region (333-340) as the primary aggregation-critical segment, and a second region at the extreme N-terminus (first 59 amino acids, optionally expressed) can independently induce aggregation; the 597 aa form lacking these 59 aa has reduced aggregation propensity. Insoluble TRIOBP-1 is more prevalent in brains from both schizophrenia and major depressive disorder patients compared to controls.","method":"Truncation mutagenesis, insolubility assay (high-stringency), expression in neuroblastoma cells, post-mortem brain fractionation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain mapping via truncation in cells, replicated brain insolubility finding across two psychiatric conditions; single lab","pmids":["36232351"],"is_preprint":false},{"year":2023,"finding":"TRIOBP interacts with TRIO RhoGEF and promotes abnormal epithelial-mesenchymal crosstalk in pulmonary fibrosis. TRIOBP knockdown inhibits epithelial cell proliferation and attenuates fibroblast activation. The TRIOBP-TRIO interaction modulates nucleocytoplasmic translocation of β-catenin. The miR-29b–TRIOBP–TRIO–β-catenin axis regulates lung regeneration and fibrosis.","method":"siRNA knockdown, co-immunoprecipitation, β-catenin nuclear translocation assay, in vivo fibrosis model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD with defined cellular phenotypes, β-catenin localization assay; single lab","pmids":["38157020"],"is_preprint":false},{"year":2025,"finding":"In renal fibrosis, retinoic acid (RA) upregulates RAI14, which binds and stabilizes TRIOBP by preventing its HECTD1-mediated ubiquitination and degradation. Stabilized TRIOBP enhances F-actin assembly and cytoskeletal tension, leading to YAP nuclear translocation and activation of profibrotic gene programs. Genetic ablation of RAI14 significantly attenuates renal fibrosis in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/genetic knockdown, F-actin assembly assay, YAP nuclear translocation assay, in vivo knockout mouse, spatial metabolomics, single-cell transcriptomics","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, in vivo KO) in a single study; single lab","pmids":["41242366"],"is_preprint":false},{"year":2025,"finding":"SYISL lncRNA acts as a competing endogenous RNA (ceRNA) that directly binds miR-23a, thereby derepressing TRIOBP expression via its 3'UTR. Knockdown of TRIOBP amplifies anti-fibrotic effects of miR-23a mimics and abolishes pro-fibrotic activity of miR-23a inhibitors, establishing TRIOBP as a downstream effector of the SYISL/miR-23a axis in fibroblast-to-myofibroblast transition.","method":"RNA pulldown/luciferase reporter (3'UTR), siRNA knockdown, miRNA mimic/inhibitor assay, in vivo AAV-shRNA delivery","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR validation, epistatic rescue experiments, in vivo confirmation; single lab","pmids":["40419807"],"is_preprint":false}],"current_model":"TRIOBP encodes multiple isoforms (principally TRIOBP-1/Tara and TRIOBP-4/5) that act as F-actin binding and bundling proteins: TRIOBP-4/5 bundles actin filaments into dense rootlet structures at the base of inner ear hair cell stereocilia (essential for mechanical resilience and hearing), while TRIOBP-1 stabilizes F-actin broadly, associates with Trio RhoGEF to regulate actin remodeling and E-cadherin transcription via a Rac1–p38–Tbx3 pathway, interacts with TRF1/tankyrase 1 at centrosomes and with hERG to modulate its surface expression and cardiac repolarization, is phosphorylated by Plk1 at Thr-457 for centrosomal localization and faithful chromosome segregation, and is ubiquitinated and degraded by HECTD3/HECTD1 E3 ligases; the ANKRD24 protein organizes TRIOBP-5 within stereocilia rootlets in a mutually dependent manner, and TRIOBP isoforms also participate in fibrotic signaling through TRIO–β-catenin and RAI14–YAP mechanotransduction axes."},"narrative":{"mechanistic_narrative":"TRIOBP encodes multiple actin-associated isoforms whose unifying activity is binding, bundling, and stabilizing F-actin to control cytoskeletal architecture across tissues [PMID:11148140, PMID:20510926, PMID:23789641]. The stereocilia-specific isoforms TRIOBP-4 and TRIOBP-5 bundle actin filaments into uniquely dense rootlet structures at the base of inner ear hair cell stereocilia; this bundling, mapped to the R1 repeat motif, confers the mechanical rigidity and durability that stereocilia require, and its loss in knockout mice abolishes rootlet formation and produces profound deafness [PMID:20510926, PMID:23789641, PMID:35737845]. Rootlet assembly is organized cooperatively with ANKRD24, which rings the stereocilia insertion point and is mutually interdependent with TRIOBP-5 for correct localization [PMID:35175278]. Consistent with this essential structural role, truncating TRIOBP mutations cause autosomal recessive nonsyndromic deafness DFNB28 [PMID:16385458, PMID:16385457]. The widely expressed TRIOBP-1/Tara isoform stabilizes F-actin more broadly and acts as a signaling scaffold: it binds the Trio RhoGEF at adherens junctions, where it restrains a Rac1–p38–Tbx3 cascade to maintain E-cadherin transcription [PMID:11148140, PMID:21482718], and it cooperates with Ndel1 to drive filopodia formation and cell migration [PMID:27546710]. TRIOBP-1 additionally functions in mitosis, where Plk1 phosphorylates it at Thr-457 to direct centrosomal localization required for faithful chromosome segregation, and where it recruits TRF1 and tankyrase 1 to spindle poles [PMID:22820163, PMID:24692559]; its abundance is set by HECT-domain E3 ligase-mediated ubiquitination and degradation [PMID:18194665, PMID:41242366]. TRIOBP-1 also binds the hERG potassium channel and limits its surface expression, thereby modulating cardiac action potential repolarization [PMID:29507111]. Through the TRIOBP–Trio–β-catenin and RAI14–F-actin–YAP mechanotransduction axes, TRIOBP isoforms promote profibrotic gene programs in lung and kidney [PMID:38157020, PMID:41242366].","teleology":[{"year":2001,"claim":"Established TRIOBP-1/Tara as a direct F-actin-binding protein that physically partners with the Trio RhoGEF, defining its founding role as a cytoskeletal stabilizer.","evidence":"Yeast two-hybrid, reciprocal Co-IP, in vitro F-actin binding, and Latrunculin B resistance assays in cultured cells","pmids":["11148140"],"confidence":"High","gaps":["Did not define which actin structures are physiologically regulated in vivo","Functional consequence of the Trio interaction not yet resolved"]},{"year":2005,"claim":"Linked TRIOBP to human hearing by showing that truncating mutations in a long isoform cause DFNB28 deafness, with the protein localizing to stereocilia F-actin.","evidence":"Genetic linkage and mutation cosegregation across multiple families plus anti-TRIOBP immunolocalization in inner ear","pmids":["16385458","16385457"],"confidence":"Medium","gaps":["Localization not coupled to a functional rescue experiment","Molecular mechanism by which loss causes deafness not addressed"]},{"year":2008,"claim":"Identified HECTD3 as an E3 ligase that ubiquitinates and degrades TRIOBP-1, placing TRIOBP turnover within cell cycle control.","evidence":"In vitro pull-down, Co-IP, ubiquitination assay, and siRNA knockdown with spindle phenotype scoring","pmids":["18194665"],"confidence":"Medium","gaps":["Single lab","Multipolar spindle phenotype not directly attributed to TRIOBP accumulation"]},{"year":2010,"claim":"Defined the core mechanistic function of stereocilia TRIOBP: bundling actin into dense rootlets that provide mechanical durability, with knockout abolishing rootlets and causing deafness.","evidence":"In vitro bundling assay with purified TRIOBP-4, immunolocalization, and Triobp-knockout mice with auditory, electrophysiology, and EM analysis","pmids":["20510926"],"confidence":"High","gaps":["Did not map the actin-binding domain","Did not identify cofactors organizing rootlet geometry"]},{"year":2011,"claim":"Placed TRIOBP-1 in a junctional signaling pathway, showing it restrains a Trio-Rac1-p38-Tbx3 cascade to sustain E-cadherin transcription.","evidence":"shRNA knockdown, pharmacological and mutant rescue, Co-IP, and luciferase reporter in MDCK epithelial cells","pmids":["21482718"],"confidence":"High","gaps":["Whether the actin-binding activity is required for pathway restraint not separated","In vivo relevance of the epithelial pathway not tested"]},{"year":2012,"claim":"Showed Plk1 phosphorylates TRIOBP-1 at Thr-457 to drive centrosomal localization needed for accurate chromosome segregation, extending its role into mitosis.","evidence":"Co-IP, in vitro kinase assay, T457A phosphosite mutant, and cell cycle analysis in HeLa cells","pmids":["22820163"],"confidence":"High","gaps":["Single lab","Downstream centrosomal effectors of phosphorylated TRIOBP not identified"]},{"year":2014,"claim":"Established a mitotic scaffolding role in which TRIOBP-1 recruits TRF1 and tankyrase 1 to spindle poles, regulated by Nek2A phosphorylation.","evidence":"Reciprocal Co-IP, domain mapping, siRNA knockdown, and live-cell imaging","pmids":["24692559"],"confidence":"High","gaps":["Functional purpose of telomere protein relocalization to poles unresolved","Single lab"]},{"year":2014,"claim":"Extended TRIOBP-4/-5 cytoskeletal function to cancer cell motility through filopodia formation, and revealed isoform-specific aggregation behavior of TRIOBP-1.","evidence":"siRNA knockdown with GFP rescue and motility assays in pancreatic cancer cells; insolubility and over-expression assays in neuroblastoma cells","pmids":["25130170","25333879"],"confidence":"Medium","gaps":["Mechanism linking TRIOBP to filopodial nucleation not defined","Physiological significance of TRIOBP-1 aggregation unclear"]},{"year":2016,"claim":"Identified Ndel1 as a TRIOBP-1 partner whose complex synergistically promotes F-actin assembly and filopodia during cell migration.","evidence":"Co-IP, domain deletion, wound healing and Boyden chamber assays, and confocal microscopy","pmids":["27546710"],"confidence":"Medium","gaps":["Single study","In vivo migration context not tested"]},{"year":2017,"claim":"Dissected TRIOBP-1 coiled-coil architecture, attributing F-actin depolymerization inhibition, oligomerization, neurite outgrowth effects, and aggregation propensity to the central domain.","evidence":"Domain deletion mutagenesis with depolymerization, insolubility, and neurite outgrowth assays","pmids":["28438837"],"confidence":"Medium","gaps":["Structural basis of oligomerization not resolved","Link between aggregation and physiological function unclear"]},{"year":2018,"claim":"Revealed a cardiac role: TRIOBP-1 binds hERG and suppresses its surface expression, modulating repolarizing current and action potential.","evidence":"Y2H, FRET, Co-IP, shRNA, and patch clamp across HEK293, native cardiac tissue, and iPSC-derived cardiomyocytes","pmids":["29507111"],"confidence":"High","gaps":["Whether endogenous TRIOBP-1 levels regulate IKr physiologically not established","Trafficking step at which hERG is retained not defined"]},{"year":2018,"claim":"Positioned TRIOBP-1/-5 as effectors of an Sp1/miR-3178 axis controlling cancer cell migration and invasion.","evidence":"3'UTR luciferase, ChIP, migration/invasion assays, and overexpression rescue","pmids":["30195749"],"confidence":"Medium","gaps":["Single lab","Direct cytoskeletal mechanism downstream not dissected"]},{"year":2022,"claim":"Defined ANKRD24 as the rootlet-organizing partner of TRIOBP-5, with reciprocal interdependence required for proper stereocilia rootlet assembly and hearing.","evidence":"Super-resolution microscopy, reciprocal knockout mislocalization, and exogenous rescue with auditory testing","pmids":["35175278"],"confidence":"High","gaps":["Molecular nature of the ANKRD24-TRIOBP-5 contact not mapped to residues","How the ring geometry templates rootlet boundaries unresolved"]},{"year":2022,"claim":"Quantified the tissue-mechanical consequence of TRIOBP loss, showing disrupted radial stiffness gradients in the cochlear sensory epithelium.","evidence":"AFM nanoscale stiffness mapping and FIB/SEM in Triobp knockout mice","pmids":["35737845"],"confidence":"High","gaps":["Direct link from stiffness changes to mechanotransduction deficits not established"]},{"year":2022,"claim":"Narrowed TRIOBP-1 aggregation determinants to short N-terminal and central segments and associated insoluble TRIOBP-1 with psychiatric disease brains.","evidence":"Truncation mutagenesis with high-stringency insolubility assays and post-mortem brain fractionation","pmids":["36232351"],"confidence":"Medium","gaps":["Causality between aggregation and disease not established","Single lab"]},{"year":2023,"claim":"Connected TRIOBP-Trio signaling to fibrosis by showing the interaction modulates beta-catenin nucleocytoplasmic translocation in pulmonary epithelial-mesenchymal crosstalk.","evidence":"siRNA knockdown, Co-IP, beta-catenin translocation assay, and in vivo fibrosis model","pmids":["38157020"],"confidence":"Medium","gaps":["Whether actin bundling is required for beta-catenin regulation not separated","Single lab"]},{"year":2025,"claim":"Defined a RAI14-TRIOBP-YAP mechanotransduction axis in renal fibrosis, where RAI14 stabilizes TRIOBP against HECTD1 ubiquitination to enhance cytoskeletal tension and YAP activation.","evidence":"Co-IP, ubiquitination assay, F-actin and YAP translocation assays, and RAI14 knockout mice with multi-omics","pmids":["41242366"],"confidence":"Medium","gaps":["HECTD1 ubiquitination site on TRIOBP not mapped","Single lab"]},{"year":2025,"claim":"Established TRIOBP as a downstream effector of a SYISL/miR-23a ceRNA axis driving fibroblast-to-myofibroblast transition.","evidence":"RNA pulldown, 3'UTR luciferase, miRNA mimic/inhibitor epistasis, and in vivo AAV-shRNA delivery","pmids":["40419807"],"confidence":"Medium","gaps":["Single lab","Cytoskeletal mechanism downstream of TRIOBP in myofibroblasts not dissected"]},{"year":null,"claim":"How TRIOBP isoform-specific activities (rootlet bundling vs. signaling scaffold vs. channel regulation) are partitioned and coordinated within a single tissue, and whether aggregation has a physiological role, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model relating actin-binding repeats and coiled-coil domains to each isoform function","Causal role of TRIOBP-1 aggregation in psychiatric disease unestablished","In vivo significance of cardiac and centrosomal roles not tested in animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,7,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8,11]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,13]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,18,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":["stereocilia rootlet"],"partners":["TRIO","ANKRD24","HECTD3","TRF1","TNKS","PLK1","NDEL1","KCNH2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2D6","full_name":"TRIO and F-actin-binding protein","aliases":["Protein Tara","TRF1-associated protein of 68 kDa","Trio-associated repeat on actin"],"length_aa":2365,"mass_kda":261.4,"function":"Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization (PubMed:18194665, PubMed:28438837). May also serve as a linker protein to recruit proteins required for F-actin formation and turnover (PubMed:18194665). Essential for correct mitotic progression (PubMed:22820163, PubMed:24692559) Plays a pivotal role in the formation of stereocilia rootlets Plays a pivotal role in the formation of stereocilia rootlets","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Midbody; Chromosome, telomere","url":"https://www.uniprot.org/uniprotkb/Q9H2D6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIOBP","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3K","stoichiometry":0.2},{"gene":"PACSIN2","stoichiometry":0.2},{"gene":"PACSIN3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIOBP","total_profiled":1310},"omim":[{"mim_id":"620234","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 24; ANKRD24","url":"https://www.omim.org/entry/620234"},{"mim_id":"618638","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 3; HECTD3","url":"https://www.omim.org/entry/618638"},{"mim_id":"614647","title":"COENZYME Q6, MONOOXYGENASE; COQ6","url":"https://www.omim.org/entry/614647"},{"mim_id":"609823","title":"DEAFNESS, AUTOSOMAL RECESSIVE 28; DFNB28","url":"https://www.omim.org/entry/609823"},{"mim_id":"609761","title":"TRIO- AND F-ACTIN-BINDING PROTEIN; TRIOBP","url":"https://www.omim.org/entry/609761"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Overexpression of Tara stabilizes F-actin structures, enhances stress fibers and cortical actin, and increases cell spreading, while Tara-expressing cells show relative resistance to Latrunculin B-induced F-actin destabilization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro F-actin binding assay, Latrunculin B treatment, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus direct in vitro binding assay plus functional cellular phenotype; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"11148140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutations in a novel long isoform of TRIOBP (218 kDa) cause DFNB28 hereditary deafness. The long isoform has a restricted expression profile including cochlea, retina, and fetal brain. Antibody staining shows TRIOBP protein expression in sensory cells of the inner ear and colocalization with F-actin along the length of stereocilia.\",\n      \"method\": \"Genetic linkage/mutation analysis, RT-PCR expression profiling, immunofluorescence with anti-TRIOBP antibody\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunolocalization to stereocilia F-actin, genetic mapping, but localization not coupled to functional rescue experiment\",\n      \"pmids\": [\"16385458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Six distinct TRIOBP mutant alleles (four nonsense, two frameshift) in exon 6 cosegregate with autosomal recessive nonsyndromic deafness across seven families, establishing TRIOBP as the DFNB28 gene.\",\n      \"method\": \"Genetic linkage analysis, mutation screening, cosegregation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic cosegregation in multiple families; no direct molecular mechanism experiment\",\n      \"pmids\": [\"16385457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HECTD3, a HECT-domain E3 ubiquitin ligase, directly binds TRIOBP-1/Tara in vitro and forms a complex in vivo. HECTD3 overexpression enhances ubiquitination of Tara and promotes its degradation; siRNA depletion of HECTD3 decreases Tara degradation. HECTD3 depletion also leads to multipolar spindle formation, suggesting that HECTD3-mediated ubiquitination and degradation of Tara facilitates cell cycle progression.\",\n      \"method\": \"In vitro pull-down, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, confocal microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed in vitro and in vivo, functional ubiquitination assay with gain- and loss-of-function, single lab\",\n      \"pmids\": [\"18194665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIOBP isoform 4 (TRIOBP-4) bundles actin filaments into uniquely dense bundles in vitro resembling stereocilia rootlets. TRIOBP localizes specifically to rootlets of inner ear hair cell stereocilia. Triobp-knockout mice (Triobp(Δex8/Δex8)) are profoundly deaf; their stereocilia develop normally but fail to form rootlets and are easier to deflect and damage. Thus TRIOBP F-actin bundling provides mechanical durability and rigidity to stereocilia.\",\n      \"method\": \"In vitro F-actin bundling assay with purified TRIOBP-4, immunolocalization, knockout mouse model with auditory and electrophysiology testing, electron microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of actin bundling with purified protein, confirmed by knockout mouse phenotype with direct structural and functional measurements; replicated by subsequent work\",\n      \"pmids\": [\"20510926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tara is enriched at E-cadherin-based adherens junctions. Tara knockdown in MDCK cells activates Rac1 through the Trio RhoGEF (which binds E-cadherin), leading to increased p38 phosphorylation and phosphorylation of Tbx3, a transcriptional E-cadherin repressor, thereby decreasing E-cadherin transcription. E-cadherin loss is rescued by ITX3 (Trio RhoGEF inhibitor), SB203580 (p38 inhibitor), or dephosphomimetic Tbx3. Tara also modulates circumferential actin-belt density and epithelial cyst morphology.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, pharmacological inhibition, phosphomimetic/dephosphomimetic mutant rescue, confocal microscopy, luciferase reporter\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, pharmacological rescue, mutant rescue, Co-IP) in a single rigorous study establishing pathway placement\",\n      \"pmids\": [\"21482718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polo-like kinase 1 (Plk1) interacts with and phosphorylates Tara at Thr-457 in vivo and in vitro. This Plk1-dependent phosphorylation is required for centrosomal localization of Tara. A non-phosphorylatable Tara mutant (T457A) causes aberrant mitotic delay in HeLa cells, demonstrating that Plk1-mediated phosphorylation of Tara at Thr-457 is required for faithful chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphosite mutagenesis, confocal microscopy, cell cycle analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in vivo phosphorylation site mutagenesis with functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22820163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The R1 repeat motif is the major actin-binding domain of TRIOBP-4. Deletion of both R1 and R2 motifs completely abolishes actin-binding and bundling activities and impairs localization to cellular actin structures. Deletion of R2 alone retains F-actin bundling and actin colocalization. R1-deleted TRIOBP-4 (consisting mainly of R2) forms only thin F-actin bundles in vitro and fails to colocalize with actin filaments in cells.\",\n      \"method\": \"Actin cosedimentation assay, in vitro F-actin bundling assay, electron microscopy, fluorescence microscopy, deletion mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with deletion mutants, multiple orthogonal structural and cellular readouts, single lab\",\n      \"pmids\": [\"23789641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TAP68 (TRIOBP-1) interacts with TRF1 in mitotic cells. TAP68 co-localizes with TRF1 to telomeres during interphase. After nuclear envelope breakdown, TAP68 translocates to spindle poles and recruits TRF1. Nek2A-dependent phosphorylation of TAP68 at Thr-221 coincides with its dissociation from telomeres. The first coiled-coil domain of TAP68 is responsible for binding and recruiting TRF1 and tankyrase 1 to the centrosome. siRNA depletion of TAP68 blocks centrosomal localization of TRF1 and tankyrase 1 and perturbs chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain deletion mapping, immunofluorescence microscopy, live cell imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, siRNA phenotype with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"24692559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIOBP-4 and TRIOBP-5 are upregulated in pancreatic carcinoma cells. Knockdown of TRIOBP-4/-5 leads to loss of filopodia and decreased cell motility; re-expression of GFP-TRIOBP-4 or -5 restores filopodial formation in TRIOBP-4/-5-deficient PANC-1 cells, demonstrating a role in promoting cell motility via regulation of filopodia actin structures.\",\n      \"method\": \"siRNA knockdown, GFP-tagged rescue expression, confocal microscopy, wound healing/motility assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phenotype and rescue experiment; single lab\",\n      \"pmids\": [\"25130170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIOBP-1 has a high aggregation propensity when over-expressed in neuroblastoma cells, whereas the TRIOBP-4 isoform does not. Endogenous TRIOBP-1 can spontaneously aggregate, doing so more in post-mitotic cell cultures. Aggregated TRIOBP-1 affects cell morphology in Neuroscreen-1 cells.\",\n      \"method\": \"Over-expression in neuroblastoma/NS-1 cells, insolubility assay, immunofluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cellular aggregation assay with isoform comparison and morphological readout; single lab\",\n      \"pmids\": [\"25333879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ndel1 interacts physically with Tara (TRIOBP-1). Ndel1- or Tara-deficient cells are defective in cell migration. Tara overexpression accumulates Ndel1 at the cell periphery, co-localizing with F-actin; this redistribution requires the Ndel1-interacting domain of Tara. Co-expression of Ndel1 and Tara causes synergistic increases in F-actin levels and filopodia formation, indicating that the Ndel1-Tara complex regulates actin remodeling during cell movement.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, wound healing assay, Boyden chamber assay, confocal microscopy, siRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional experiments with domain deletion and migration assays; single lab, single study\",\n      \"pmids\": [\"27546710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIOBP-1 possesses two distinct coiled-coil domains (central and C-terminal). The central domain inhibits F-actin depolymerization, mediates oligomerization of TRIOBP-1, and affects neurite outgrowth along with the N-terminal PH domain. The aggregation propensity of TRIOBP-1 arises from its central domain, with an 8-25 amino acid linker region (around residues 324-348) between the first two coiled coils being essential for aggregate formation.\",\n      \"method\": \"Domain deletion mutagenesis, F-actin depolymerization assay, insolubility assay in neuroblastoma cells, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mapping with multiple functional readouts; single lab\",\n      \"pmids\": [\"28438837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIOBP-1 interacts directly with the hERG cardiac potassium channel protein (identified by yeast two-hybrid and confirmed by FRET and co-immunoprecipitation in HEK293 cells and native cardiac tissue). TRIOBP-1 overexpression reduces hERG surface expression and current density (IKr); shRNA knockdown of TRIOBP-1 increases hERG protein levels. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression causes intracellular co-sequestration of hERG, reduces native IKr, and disrupts action potential repolarization.\",\n      \"method\": \"Yeast two-hybrid, FRET, co-immunoprecipitation, shRNA knockdown, whole-cell patch clamp, immunolabeling, human iPSC-derived cardiomyocytes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction confirmed by three orthogonal methods (Y2H, FRET, Co-IP) in multiple cell systems including native tissue; functional readout via electrophysiology\",\n      \"pmids\": [\"29507111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sp1 transcriptionally suppresses miR-3178, and miR-3178 directly targets the 3' UTR of TRIOBP-1 and TRIOBP-5, reducing their expression. Overexpression of TRIOBP-1 rescues the inhibitory effect of miR-3178 on cell migration and invasion, establishing TRIOBP-1 as a downstream effector of the Sp1/miR-3178 axis in cancer cell metastasis.\",\n      \"method\": \"Luciferase reporter assay (3'UTR), ChIP, migration/invasion assays, overexpression rescue\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR luciferase validates direct miRNA targeting, rescue experiment confirms TRIOBP as effector; single lab\",\n      \"pmids\": [\"30195749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANKRD24 concentrates at the stereocilia insertion point forming a ring at the junction between lower and upper rootlets, where it surrounds and binds TRIOBP-5 which bundles rootlet F-actin. TRIOBP-5 is mislocalized in Ankrd24KO/KO hair cells, and ANKRD24 no longer localizes with rootlets in mice lacking TRIOBP-5; exogenous DsRed-TRIOBP-5 restores endogenous ANKRD24 to rootlets, demonstrating mutual interdependence. Ankrd24KO/KO mice show progressive hearing loss and increased susceptibility to overstimulation.\",\n      \"method\": \"Super-resolution microscopy, knockout mouse models, exogenous rescue expression, immunolocalization, auditory function testing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — super-resolution localization, reciprocal knockout mislocalization phenotypes, and exogenous rescue; multiple orthogonal methods\",\n      \"pmids\": [\"35175278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIOBP deficiency (knockout of isoforms 4 and 5 or isoform 5 alone) significantly disrupts the magnitude and orientation of bidirectional radial stiffness gradients in the cochlear sensory epithelium and causes ultrastructural changes in supporting cell phalangeal microfilaments and hair cell cuticular plate F-actin bundles, as measured by nanoscale AFM mapping.\",\n      \"method\": \"Atomic force microscopy (AFM) stiffness mapping, focused ion beam/scanning electron microscopy, Triobp knockout mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct nanomechanical measurement with sub-100-nm resolution in multiple knockout mouse models; single study with multiple orthogonal structural methods\",\n      \"pmids\": [\"35737845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIOBP-1 aggregation in neuroblastoma cells can be narrowed to an 8 amino acid region (333-340) as the primary aggregation-critical segment, and a second region at the extreme N-terminus (first 59 amino acids, optionally expressed) can independently induce aggregation; the 597 aa form lacking these 59 aa has reduced aggregation propensity. Insoluble TRIOBP-1 is more prevalent in brains from both schizophrenia and major depressive disorder patients compared to controls.\",\n      \"method\": \"Truncation mutagenesis, insolubility assay (high-stringency), expression in neuroblastoma cells, post-mortem brain fractionation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain mapping via truncation in cells, replicated brain insolubility finding across two psychiatric conditions; single lab\",\n      \"pmids\": [\"36232351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIOBP interacts with TRIO RhoGEF and promotes abnormal epithelial-mesenchymal crosstalk in pulmonary fibrosis. TRIOBP knockdown inhibits epithelial cell proliferation and attenuates fibroblast activation. The TRIOBP-TRIO interaction modulates nucleocytoplasmic translocation of β-catenin. The miR-29b–TRIOBP–TRIO–β-catenin axis regulates lung regeneration and fibrosis.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, β-catenin nuclear translocation assay, in vivo fibrosis model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD with defined cellular phenotypes, β-catenin localization assay; single lab\",\n      \"pmids\": [\"38157020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In renal fibrosis, retinoic acid (RA) upregulates RAI14, which binds and stabilizes TRIOBP by preventing its HECTD1-mediated ubiquitination and degradation. Stabilized TRIOBP enhances F-actin assembly and cytoskeletal tension, leading to YAP nuclear translocation and activation of profibrotic gene programs. Genetic ablation of RAI14 significantly attenuates renal fibrosis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/genetic knockdown, F-actin assembly assay, YAP nuclear translocation assay, in vivo knockout mouse, spatial metabolomics, single-cell transcriptomics\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, in vivo KO) in a single study; single lab\",\n      \"pmids\": [\"41242366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SYISL lncRNA acts as a competing endogenous RNA (ceRNA) that directly binds miR-23a, thereby derepressing TRIOBP expression via its 3'UTR. Knockdown of TRIOBP amplifies anti-fibrotic effects of miR-23a mimics and abolishes pro-fibrotic activity of miR-23a inhibitors, establishing TRIOBP as a downstream effector of the SYISL/miR-23a axis in fibroblast-to-myofibroblast transition.\",\n      \"method\": \"RNA pulldown/luciferase reporter (3'UTR), siRNA knockdown, miRNA mimic/inhibitor assay, in vivo AAV-shRNA delivery\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR validation, epistatic rescue experiments, in vivo confirmation; single lab\",\n      \"pmids\": [\"40419807\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIOBP encodes multiple isoforms (principally TRIOBP-1/Tara and TRIOBP-4/5) that act as F-actin binding and bundling proteins: TRIOBP-4/5 bundles actin filaments into dense rootlet structures at the base of inner ear hair cell stereocilia (essential for mechanical resilience and hearing), while TRIOBP-1 stabilizes F-actin broadly, associates with Trio RhoGEF to regulate actin remodeling and E-cadherin transcription via a Rac1–p38–Tbx3 pathway, interacts with TRF1/tankyrase 1 at centrosomes and with hERG to modulate its surface expression and cardiac repolarization, is phosphorylated by Plk1 at Thr-457 for centrosomal localization and faithful chromosome segregation, and is ubiquitinated and degraded by HECTD3/HECTD1 E3 ligases; the ANKRD24 protein organizes TRIOBP-5 within stereocilia rootlets in a mutually dependent manner, and TRIOBP isoforms also participate in fibrotic signaling through TRIO–β-catenin and RAI14–YAP mechanotransduction axes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIOBP encodes multiple actin-associated isoforms whose unifying activity is binding, bundling, and stabilizing F-actin to control cytoskeletal architecture across tissues [#0, #4, #7]. The stereocilia-specific isoforms TRIOBP-4 and TRIOBP-5 bundle actin filaments into uniquely dense rootlet structures at the base of inner ear hair cell stereocilia; this bundling, mapped to the R1 repeat motif, confers the mechanical rigidity and durability that stereocilia require, and its loss in knockout mice abolishes rootlet formation and produces profound deafness [#4, #7, #16]. Rootlet assembly is organized cooperatively with ANKRD24, which rings the stereocilia insertion point and is mutually interdependent with TRIOBP-5 for correct localization [#15]. Consistent with this essential structural role, truncating TRIOBP mutations cause autosomal recessive nonsyndromic deafness DFNB28 [#1, #2]. The widely expressed TRIOBP-1/Tara isoform stabilizes F-actin more broadly and acts as a signaling scaffold: it binds the Trio RhoGEF at adherens junctions, where it restrains a Rac1\\u2013p38\\u2013Tbx3 cascade to maintain E-cadherin transcription [#0, #5], and it cooperates with Ndel1 to drive filopodia formation and cell migration [#11]. TRIOBP-1 additionally functions in mitosis, where Plk1 phosphorylates it at Thr-457 to direct centrosomal localization required for faithful chromosome segregation, and where it recruits TRF1 and tankyrase 1 to spindle poles [#6, #8]; its abundance is set by HECT-domain E3 ligase-mediated ubiquitination and degradation [#3, #19]. TRIOBP-1 also binds the hERG potassium channel and limits its surface expression, thereby modulating cardiac action potential repolarization [#13]. Through the TRIOBP\\u2013Trio\\u2013\\u03b2-catenin and RAI14\\u2013F-actin\\u2013YAP mechanotransduction axes, TRIOBP isoforms promote profibrotic gene programs in lung and kidney [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established TRIOBP-1/Tara as a direct F-actin-binding protein that physically partners with the Trio RhoGEF, defining its founding role as a cytoskeletal stabilizer.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, in vitro F-actin binding, and Latrunculin B resistance assays in cultured cells\",\n      \"pmids\": [\"11148140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which actin structures are physiologically regulated in vivo\", \"Functional consequence of the Trio interaction not yet resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked TRIOBP to human hearing by showing that truncating mutations in a long isoform cause DFNB28 deafness, with the protein localizing to stereocilia F-actin.\",\n      \"evidence\": \"Genetic linkage and mutation cosegregation across multiple families plus anti-TRIOBP immunolocalization in inner ear\",\n      \"pmids\": [\"16385458\", \"16385457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization not coupled to a functional rescue experiment\", \"Molecular mechanism by which loss causes deafness not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified HECTD3 as an E3 ligase that ubiquitinates and degrades TRIOBP-1, placing TRIOBP turnover within cell cycle control.\",\n      \"evidence\": \"In vitro pull-down, Co-IP, ubiquitination assay, and siRNA knockdown with spindle phenotype scoring\",\n      \"pmids\": [\"18194665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Multipolar spindle phenotype not directly attributed to TRIOBP accumulation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the core mechanistic function of stereocilia TRIOBP: bundling actin into dense rootlets that provide mechanical durability, with knockout abolishing rootlets and causing deafness.\",\n      \"evidence\": \"In vitro bundling assay with purified TRIOBP-4, immunolocalization, and Triobp-knockout mice with auditory, electrophysiology, and EM analysis\",\n      \"pmids\": [\"20510926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the actin-binding domain\", \"Did not identify cofactors organizing rootlet geometry\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed TRIOBP-1 in a junctional signaling pathway, showing it restrains a Trio-Rac1-p38-Tbx3 cascade to sustain E-cadherin transcription.\",\n      \"evidence\": \"shRNA knockdown, pharmacological and mutant rescue, Co-IP, and luciferase reporter in MDCK epithelial cells\",\n      \"pmids\": [\"21482718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the actin-binding activity is required for pathway restraint not separated\", \"In vivo relevance of the epithelial pathway not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed Plk1 phosphorylates TRIOBP-1 at Thr-457 to drive centrosomal localization needed for accurate chromosome segregation, extending its role into mitosis.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, T457A phosphosite mutant, and cell cycle analysis in HeLa cells\",\n      \"pmids\": [\"22820163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Downstream centrosomal effectors of phosphorylated TRIOBP not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a mitotic scaffolding role in which TRIOBP-1 recruits TRF1 and tankyrase 1 to spindle poles, regulated by Nek2A phosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, siRNA knockdown, and live-cell imaging\",\n      \"pmids\": [\"24692559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional purpose of telomere protein relocalization to poles unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended TRIOBP-4/-5 cytoskeletal function to cancer cell motility through filopodia formation, and revealed isoform-specific aggregation behavior of TRIOBP-1.\",\n      \"evidence\": \"siRNA knockdown with GFP rescue and motility assays in pancreatic cancer cells; insolubility and over-expression assays in neuroblastoma cells\",\n      \"pmids\": [\"25130170\", \"25333879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TRIOBP to filopodial nucleation not defined\", \"Physiological significance of TRIOBP-1 aggregation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Ndel1 as a TRIOBP-1 partner whose complex synergistically promotes F-actin assembly and filopodia during cell migration.\",\n      \"evidence\": \"Co-IP, domain deletion, wound healing and Boyden chamber assays, and confocal microscopy\",\n      \"pmids\": [\"27546710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"In vivo migration context not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected TRIOBP-1 coiled-coil architecture, attributing F-actin depolymerization inhibition, oligomerization, neurite outgrowth effects, and aggregation propensity to the central domain.\",\n      \"evidence\": \"Domain deletion mutagenesis with depolymerization, insolubility, and neurite outgrowth assays\",\n      \"pmids\": [\"28438837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of oligomerization not resolved\", \"Link between aggregation and physiological function unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a cardiac role: TRIOBP-1 binds hERG and suppresses its surface expression, modulating repolarizing current and action potential.\",\n      \"evidence\": \"Y2H, FRET, Co-IP, shRNA, and patch clamp across HEK293, native cardiac tissue, and iPSC-derived cardiomyocytes\",\n      \"pmids\": [\"29507111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous TRIOBP-1 levels regulate IKr physiologically not established\", \"Trafficking step at which hERG is retained not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned TRIOBP-1/-5 as effectors of an Sp1/miR-3178 axis controlling cancer cell migration and invasion.\",\n      \"evidence\": \"3'UTR luciferase, ChIP, migration/invasion assays, and overexpression rescue\",\n      \"pmids\": [\"30195749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct cytoskeletal mechanism downstream not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined ANKRD24 as the rootlet-organizing partner of TRIOBP-5, with reciprocal interdependence required for proper stereocilia rootlet assembly and hearing.\",\n      \"evidence\": \"Super-resolution microscopy, reciprocal knockout mislocalization, and exogenous rescue with auditory testing\",\n      \"pmids\": [\"35175278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the ANKRD24-TRIOBP-5 contact not mapped to residues\", \"How the ring geometry templates rootlet boundaries unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Quantified the tissue-mechanical consequence of TRIOBP loss, showing disrupted radial stiffness gradients in the cochlear sensory epithelium.\",\n      \"evidence\": \"AFM nanoscale stiffness mapping and FIB/SEM in Triobp knockout mice\",\n      \"pmids\": [\"35737845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from stiffness changes to mechanotransduction deficits not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Narrowed TRIOBP-1 aggregation determinants to short N-terminal and central segments and associated insoluble TRIOBP-1 with psychiatric disease brains.\",\n      \"evidence\": \"Truncation mutagenesis with high-stringency insolubility assays and post-mortem brain fractionation\",\n      \"pmids\": [\"36232351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between aggregation and disease not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected TRIOBP-Trio signaling to fibrosis by showing the interaction modulates beta-catenin nucleocytoplasmic translocation in pulmonary epithelial-mesenchymal crosstalk.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, beta-catenin translocation assay, and in vivo fibrosis model\",\n      \"pmids\": [\"38157020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether actin bundling is required for beta-catenin regulation not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a RAI14-TRIOBP-YAP mechanotransduction axis in renal fibrosis, where RAI14 stabilizes TRIOBP against HECTD1 ubiquitination to enhance cytoskeletal tension and YAP activation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, F-actin and YAP translocation assays, and RAI14 knockout mice with multi-omics\",\n      \"pmids\": [\"41242366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HECTD1 ubiquitination site on TRIOBP not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established TRIOBP as a downstream effector of a SYISL/miR-23a ceRNA axis driving fibroblast-to-myofibroblast transition.\",\n      \"evidence\": \"RNA pulldown, 3'UTR luciferase, miRNA mimic/inhibitor epistasis, and in vivo AAV-shRNA delivery\",\n      \"pmids\": [\"40419807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Cytoskeletal mechanism downstream of TRIOBP in myofibroblasts not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIOBP isoform-specific activities (rootlet bundling vs. signaling scaffold vs. channel regulation) are partitioned and coordinated within a single tissue, and whether aggregation has a physiological role, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model relating actin-binding repeats and coiled-coil domains to each isoform function\", \"Causal role of TRIOBP-1 aggregation in psychiatric disease unestablished\", \"In vivo significance of cardiac and centrosomal roles not tested in animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 7, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 18, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"stereocilia rootlet\"],\n    \"partners\": [\"TRIO\", \"ANKRD24\", \"HECTD3\", \"TRF1\", \"TNKS\", \"PLK1\", \"NDEL1\", \"KCNH2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}