TRIP4 (Activating Signal Cointegrator 1, ASC-1; thyroid receptor-interacting protein 4) is a C4-type zinc-finger protein that functions in two distinct contexts. As a subunit of the ASC-1 / RQC-trigger (RQT) complex (with ASCC1, ASCC2 and the ASCC3 helicase), it acts in ribosome-associated quality control, where the complex recognizes K63-polyubiquitinated collided ribosomes and drives splitting/disassembly of the collided (disome) ribosomes so that the obstructing nascent chain can be targeted for degradation. Separately, TRIP4 acts as a nuclear transcriptional coactivator/cointegrator; through its zinc-finger transactivation domain it binds nuclear receptors (thyroid hormone receptor, estrogen receptor ESR1, androgen receptor), basal transcription factors (TBP, TFIIA), and coactivators (SRC-1/NCOA1, CBP/EP300), and potentiates nuclear-receptor-, SRF-, AP-1- and NF-kappaB-mediated transcription. Its coactivator activity is regulated by UFM1 modification (ufmylation); ligand-bound nuclear receptors displace the UFM1 protease UFSP2 from TRIP4, allowing ufmylation that promotes recruitment of EP300/NCOA1 and assembly of an active coactivator complex. TRIP4 is predominantly nuclear (cytoplasmic under serum deprivation; colocalizes with NEK6 at the centrosome). Biallelic loss-of-function variants in TRIP4 cause severe congenital neuromuscular disease (spinal muscular atrophy with congenital bone fractures, SMABF1; and congenital muscular dystrophy, Davignon-Chauveau type).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003713 transcription coactivator activity | IBA GO_REF:0000033 | ACCEPT | Summary: TRIP4/ASC-1 is a transcriptional coactivator/cointegrator that potentiates nuclear-receptor- and other transcription-factor-mediated transcription; this is one of its two well-supported core molecular functions. Reason: Transcription coactivator activity is directly demonstrated experimentally (PMID:10454579, PMID:25219498) and corroborated by phylogenetic inference; it is a genuine core function of TRIP4. Supporting Evidence: PMID:12077347 ASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. |
| GO:0030520 estrogen receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TRIP4 coactivates ligand-bound estrogen receptor ESR1, and its ufmylation is required for ERalpha transactivation; participation in estrogen receptor signaling is well supported. Reason: Directly supported experimentally (TRIP4/ASC1 ufmylation is crucial for ERalpha transactivation) and by phylogenetic inference. Supporting Evidence: PMID:25219498 ASC1 is a key step for ERΞ± transactivation in response to 17Ξ²-estradiol (E2). |
| GO:0072344 rescue of stalled cytosolic ribosome | IBA GO_REF:0000033 | ACCEPT | Summary: As part of the ASC-1/RQT complex, TRIP4 acts in resolution of stalled/collided ribosomes (ribosome-associated quality control), splitting collided ribosomes to allow rescue. A core biological process. Reason: Strongly supported by multiple experimental studies (PMID:32099016, PMID:32579943, PMID:36302773) showing the ASC-1/RQT complex disassembles collided ribosomes; consistent with the phylogenetic inference. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0180022 RQC-trigger complex | IBA GO_REF:0000033 | ACCEPT | Summary: TRIP4 is a constituent subunit of the RQC-trigger (RQT)/ASC-1 complex, the core cellular-component context for its ribosome-quality-control function. Reason: Directly demonstrated (TRIP4 is identified in the RQT complex with ASCC2 and ASCC3) and supported phylogenetically. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4 |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: TRIP4 is active in the nucleus as a transcriptional coactivator; nuclear localization is well established experimentally. Reason: Nuclear localization and activity are directly documented (PMID:10454579, PMID:12077347) and supported by phylogenetic inference. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0045893 positive regulation of DNA-templated transcription | IBA GO_REF:0000033 | ACCEPT | Summary: TRIP4 positively regulates transcription as a coactivator; well supported. Reason: Positive regulation of transcription is the process outcome of TRIP4's coactivator activity, directly demonstrated and phylogenetically inferred. Supporting Evidence: PMID:25219498 ASC1 is a key step for ERΞ± transactivation in response to 17Ξ²-estradiol (E2). |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic nuclear localization, consistent with strong experimental evidence. Reason: Agrees with multiple IDA/EXP nuclear localization annotations. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic centrosome localization, corroborated by direct evidence that TRIP4 colocalizes with NEK6 at the centrosome. A specialized, context-specific localization. Reason: Centrosomal localization is experimentally documented (NEK6 colocalization) but is peripheral to TRIP4's core transcriptional and RQC functions. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Colocalizes with NEK6 in the centrosome |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic cytosolic localization, consistent with the cytosolic pool where the ASC-1/RQT complex acts on collided ribosomes and with cytoplasmic localization under serum deprivation. Reason: Cytosolic localization is supported experimentally (PMID:10454579) and is the compartment for TRIP4's ribosome-quality-control role. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Cytoplasm, cytosol |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: TRIP4 has a C4-type zinc finger that binds zinc and mediates its protein interactions (with nuclear receptors, coactivators and UFSP2). Reason: Zinc binding by the C4-type zinc finger is a structural molecular function underlying TRIP4's interaction surface; supported by domain annotation. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt The C4-type zinc finger mediates a competitive interaction with UFSP2 and ligand-bound nuclear receptors. |
| GO:0072344 rescue of stalled cytosolic ribosome | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of rescue of stalled cytosolic ribosome, strongly corroborated by experimental evidence for the ASC-1/RQT complex. Reason: Agrees with multiple IDA studies; a core biological process of TRIP4. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0180022 RQC-trigger complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of RQC-trigger complex membership, corroborated experimentally. Reason: Agrees with IDA/IBA RQT-complex annotations; core cellular component. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4 |
| GO:0045661 regulation of myoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (mouse ortholog) annotation of regulation of myoblast differentiation; TRIP4 is implicated in late myogenic differentiation and its loss causes congenital muscle disease. Reason: A plausible role inferred from the mouse ortholog and consistent with the muscle-disease phenotype, but downstream of and not equivalent to TRIP4's core molecular functions. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt May play a role in late myogenic differentiation |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) nucleoplasmic localization, consistent with TRIP4's nuclear coactivator role. Reason: Agrees with experimental nuclear localization; appropriate cellular component for the transcriptional function. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Direct immunofluorescence (HPA) localization to nuclear bodies, a sub-nuclear compartment consistent with the nuclear coactivator function. Reason: A genuine sub-nuclear localization from imaging, but more granular than needed for TRIP4's core function; retained as non-core. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948291 | ACCEPT | Summary: Reactome curated cytosolic localization (RQC pathway), consistent with the site of the ASC-1/RQT complex action on collided ribosomes. Reason: Cytosol is the compartment where TRIP4 acts in ribosome-associated quality control; agrees with experimental localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948300 | ACCEPT | Summary: Reactome curated cytosolic localization (RQC pathway), redundant with the other cytosol annotations. Reason: Consistent with TRIP4's cytosolic ribosome-quality-control site of action. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Cytoplasm, cytosol |
| GO:0032790 ribosome disassembly | NAS PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: The ASC-1/RQT complex disassembles collided ribosomes; ribosome disassembly captures the splitting of the stalled (disome) ribosome by the complex. Reason: Directly supported by experimental work (PMID:32579943, PMID:36302773) showing the ASC-1/RQT complex drives ribosomal subunit dissociation of collided ribosomes. Supporting Evidence: PMID:32579943 disassembly of collided ribosomes. |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | NAS PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: TRIP4/ASC-1 acts in the ribosome-associated quality control (RQC) pathway, which degrades nascent peptide chains during problematic translation in a ubiquitin-dependent manner. Reason: The RQT complex recognizes ubiquitinated collided ribosomes to initiate RQC, leading to ubiquitin-dependent degradation of the nascent chain; well supported. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0005634 nucleus | EXP PMID:20873783 Characterization of hNek6 interactome reveals an important r... | ACCEPT | Summary: Experimental nuclear localization, consistent with TRIP4's coactivator role. Reason: Direct experimental support for nuclear localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0032790 ribosome disassembly | IDA PMID:32579943 The ASC-1 Complex Disassembles Collided Ribosomes. | ACCEPT | Summary: Direct evidence that the ASC-1 complex disassembles collided ribosomes, the central mechanistic step of TRIP4's RQC function. Reason: Directly demonstrated experimentally; core process of the ASC-1/RQT complex. Supporting Evidence: PMID:32579943 disassembly of collided ribosomes. |
| GO:0032790 ribosome disassembly | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: Direct evidence that the hRQT/ASC-1 complex mediates ribosomal subunit dissociation of ubiquitinated collided ribosomes. Reason: Directly demonstrated experimentally; core process. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:32579943 The ASC-1 Complex Disassembles Collided Ribosomes. | ACCEPT | Summary: Direct evidence that the ASC-1 complex resolves collided ribosomes, rescuing stalled ribosomes via disassembly. Reason: Directly demonstrated; core process of TRIP4's ribosome-quality-control role. Supporting Evidence: PMID:32579943 disassembly of collided ribosomes. |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: Direct evidence (disome collision study) that the hRQT/ASC-1 complex initiates rescue of collided ribosomes by subunit dissociation. Reason: Directly demonstrated; core process. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0072344 rescue of stalled cytosolic ribosome | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: Mutational/functional evidence that TRIP4 within the RQT complex is required for ribosome-associated quality control of stalled ribosomes. Reason: Supported by the identification and functional characterization of the RQT complex in mammalian RQC. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: Functional evidence that TRIP4/RQT participates in ubiquitin-dependent degradation of nascent chains during RQC. Reason: Supported by RQT-complex characterization in mammalian RQC. Supporting Evidence: PMID:36302773 the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation. |
| GO:0005813 centrosome | IDA PMID:20873783 Characterization of hNek6 interactome reveals an important r... | KEEP AS NON CORE | Summary: Direct evidence that TRIP4 colocalizes with NEK6 at the centrosome, a specialized localization. Reason: Genuine colocalization (NEK6 interactome study) but peripheral to TRIP4's core transcriptional and RQC functions. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Colocalizes with NEK6 in the centrosome |
| GO:0019901 protein kinase binding | IPI PMID:20873783 Characterization of hNek6 interactome reveals an important r... | KEEP AS NON CORE | Summary: Interaction with the protein kinase NEK6 (Q9HC98), which phosphorylates TRIP4. A real but auxiliary binding function. Reason: Documented NEK6 interaction (TRIP4 is phosphorylated by NEK6), informative but not a core molecular function of TRIP4. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with NEK6 |
| GO:0032991 protein-containing complex | IDA PMID:20873783 Characterization of hNek6 interactome reveals an important r... | MARK AS OVER ANNOTATED | Summary: Generic protein-containing complex membership. TRIP4 is part of defined complexes (ASC-1/RQT coactivator complexes); the specific RQC-trigger complex term is more informative. Reason: The bare "protein-containing complex" is uninformative; TRIP4's complexes are specifically captured by GO:0180022 (RQC-trigger complex) and the ASC-1 coactivator complex. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 |
| GO:0045661 regulation of myoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity-based annotation of regulation of myoblast differentiation, consistent with the muscle-disease phenotype but downstream of TRIP4's core functions. Reason: Plausible role inferred from the ortholog and the congenital muscle phenotype, but not a core molecular function. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt May play a role in late myogenic differentiation |
| GO:0180022 RQC-trigger complex | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | ACCEPT | Summary: TRIP4 is a subunit of the ASC-1 complex (TRIP4/ASCC1/ASCC2/ASCC3); this complex is the RQC-trigger (RQT) complex that acts in ribosome-associated quality control. Reason: Directly demonstrated complex membership; the ASC-1 complex is the RQT complex, a core cellular component. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | ACCEPT | Summary: TRIP4/ASC-1 regulates transcription, stimulating transactivation by SRF, AP-1 and NF-kappaB and relieving transrepression between nuclear receptors and AP-1/NF-kappaB. Reason: Directly demonstrated transcriptional regulatory activity; consistent with the coactivator core function. Supporting Evidence: PMID:12077347 stimulates transactivation by serum response factor (SRF), activating protein 1 (AP-1), and nuclear factor kappaB (NF-kappaB) |
| GO:0006355 regulation of DNA-templated transcription | IMP PMID:26924529 Mutations in Subunits of the Activating Signal Cointegrator ... | ACCEPT | Summary: Functional/disease evidence linking ASC-1 complex function to transcriptional regulation; consistent with the coactivator role. Reason: Supports TRIP4's role in transcriptional regulation, demonstrated in the context of ASC-1-complex disease mutations. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Transcription coactivator which associates with nuclear |
| GO:0005634 nucleus | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | ACCEPT | Summary: Direct nuclear localization, consistent with the coactivator role. Reason: Direct experimental support for nuclear localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IDA PMID:26924529 Mutations in Subunits of the Activating Signal Cointegrator ... | ACCEPT | Summary: Direct nuclear localization, consistent with the coactivator role. Reason: Direct experimental support for nuclear localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0031594 neuromuscular junction | IMP PMID:26924529 Mutations in Subunits of the Activating Signal Cointegrator ... | KEEP AS NON CORE | Summary: TRIP4 is implicated in neuromuscular junction development; a specialized, tissue-context localization tied to the disease phenotype. Reason: Supported in the disease/neuromuscular context but peripheral to TRIP4's core molecular functions; a may-play-a-role statement. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt May play a role in the development of neuro |
| GO:0030520 estrogen receptor signaling pathway | IDA PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: Direct evidence that TRIP4/ASC1 is required for ERalpha transactivation (via ufmylation), placing it in estrogen receptor signaling. Reason: Directly demonstrated involvement in ERalpha-mediated transactivation. Supporting Evidence: PMID:25219498 ASC1 is a key step for ERΞ± transactivation in response to 17Ξ²-estradiol (E2). |
| GO:0003713 transcription coactivator activity | IMP PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4/ASC1 acts as a transcription coactivator whose ufmylation-dependent assembly of an EP300/NCOA1 coactivator complex potentiates nuclear-receptor transcription. Reason: Directly demonstrated coactivator activity; a core molecular function. Supporting Evidence: PMID:25219498 ASC1 is a key step for ERΞ± transactivation in response to 17Ξ²-estradiol (E2). |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4 positively regulates transcription, demonstrated through its requirement for ERalpha transactivation. Reason: Directly demonstrated positive transcriptional regulation. Supporting Evidence: PMID:25219498 ASC1 is a key step for ERΞ± transactivation in response to 17Ξ²-estradiol (E2). |
| GO:0005515 protein binding | IPI PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | KEEP AS NON CORE | Summary: IntAct interactions (e.g. with DDRGK1, Q15788) from the ASC1-ufmylation study. The bare protein binding term is uninformative. Reason: Records real interactions but bare protein binding is uninformative; specific binding functions (nuclear-receptor, HAT, UFM1-ligase binding) are captured separately. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with DDRGK1 and UFL1; the interaction with DDRGK1 is direct |
| GO:0030331 nuclear estrogen receptor binding | IPI PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4 binds the ligand-bound nuclear estrogen receptor ESR1 (P03372), a specific and functionally central interaction for its coactivator role. Reason: Directly documented binding to ESR1; an informative molecular function underlying TRIP4's estrogen-receptor coactivation. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with ESR1 (estrogen ligand-bound); competes with UFSP2 |
| GO:0035035 histone acetyltransferase binding | IPI PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4 binds the histone acetyltransferase EP300/CBP (Q09472), recruited to assemble the active coactivator complex. Reason: Directly documented EP300 interaction; an informative molecular function supporting the coactivator role. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with EP300 |
| GO:0002020 protease binding | IPI PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4 binds the UFM1-specific protease UFSP2 (Q9NUQ7); ligand-bound nuclear receptors compete with UFSP2 for TRIP4, regulating its ufmylation. Reason: Directly documented UFSP2 interaction; an informative and mechanistically central binding function (governs the ufmylation switch). Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with UFSP2; competes with ligand-bound ESR1 |
| GO:0005634 nucleus | IDA PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: Direct nuclear localization in the ufmylation/ERalpha study. Reason: Direct experimental support for nuclear localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0044389 ubiquitin-like protein ligase binding | IPI PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: TRIP4 binds the UFM1 E3 ligase component UFL1 (O94874) (and directly DDRGK1), consistent with TRIP4 being a ufmylation substrate. Reason: Directly documented interaction with the UFM1 ligase machinery (UFL1/DDRGK1); an informative binding function central to TRIP4 ufmylation. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Interacts with DDRGK1 and UFL1; the interaction with DDRGK1 is direct |
| GO:0005634 nucleus | IDA PMID:10454579 Activating signal cointegrator 1, a novel transcription coac... | ACCEPT | Summary: Direct nuclear localization in the original ASC-1 coactivator paper. Reason: Direct experimental support for nuclear localization. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IDA PMID:10454579 Activating signal cointegrator 1, a novel transcription coac... | ACCEPT | Summary: Direct cytoplasmic localization (under serum deprivation), consistent with the cytosolic pool where TRIP4 acts in RQC. Reason: Experimentally supported; TRIP4 relocalizes to the cytoplasm under serum deprivation, and the RQC role is cytosolic. Supporting Evidence: file:human/TRIP4/TRIP4-uniprot.txt Cytoplasmic under conditions of serum deprivation |
| GO:0016922 nuclear receptor binding | IDA PMID:10454579 Activating signal cointegrator 1, a novel transcription coac... | ACCEPT | Summary: TRIP4 binds nuclear receptors (thyroid hormone receptor, estrogen receptor, androgen receptor) via its zinc-finger transactivation domain; central to its coactivator function. Reason: Directly documented nuclear-receptor binding; a core molecular function underlying TRIP4's coactivator activity. Supporting Evidence: PMID:10454579 nuclear receptors, as demonstrated by the glutathione S-transferase pull-down assays and the yeast two-hybrid tests. |
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Download this section (compressed HTML)Q: How does TRIP4 partition between its nuclear transcription-coactivator role and its cytosolic ribosome-quality-control role, and is this regulated (e.g. by serum status, ufmylation, or NEK6 phosphorylation)?
Q: Within the RQT complex, what is TRIP4's specific mechanistic contribution to recognizing K63-ubiquitinated collided ribosomes versus the ASCC3 helicase-driven splitting step?
Q: Are the congenital neuromuscular phenotypes of TRIP4 loss caused primarily by defective RQC, defective transcriptional coactivation, or both?
Experiment: Separation-of-function mutants of TRIP4 that selectively disrupt RQT-complex incorporation versus nuclear-receptor binding, tested for ribosome-collision resolution and nuclear-receptor transactivation independently.
Experiment: Cryo-EM of the human RQT complex on a defined collided disome to localize TRIP4 and define how it couples ubiquitin recognition to ASCC3-mediated subunit dissociation.
Experiment: Patient-derived or CRISPR TRIP4-null muscle/motor-neuron models with RQC reporters and nuclear-receptor transcriptional readouts to dissect which function underlies SMABF1/MDCDC pathology.
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