id: Q15650
gene_symbol: TRIP4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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).
existing_annotations:
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: ASC-1) was originally isolated as a  transcriptional coactivator of nuclear receptors.
- term:
    id: GO:0030520
    label: estrogen receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: TRIP4 coactivates ligand-bound estrogen receptor ESR1, and its ufmylation is required for ERalpha transactivation; participation in estrogen receptor signaling is well supported.
    action: ACCEPT
    reason: Directly supported experimentally (TRIP4/ASC1 ufmylation is crucial for ERalpha transactivation) and by phylogenetic inference.
    supported_by:
    - reference_id: PMID:25219498
      supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0180022
    label: RQC-trigger complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: Directly demonstrated (TRIP4 is identified in the RQT complex with ASCC2 and ASCC3) and supported phylogenetically.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: TRIP4 is active in the nucleus as a transcriptional coactivator; nuclear localization is well established experimentally.
    action: ACCEPT
    reason: Nuclear localization and activity are directly documented (PMID:10454579, PMID:12077347) and supported by phylogenetic inference.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: TRIP4 positively regulates transcription as a coactivator; well supported.
    action: ACCEPT
    reason: Positive regulation of transcription is the process outcome of TRIP4's coactivator activity, directly demonstrated and phylogenetically inferred.
    supported_by:
    - reference_id: PMID:25219498
      supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic nuclear localization, consistent with strong experimental evidence.
    action: ACCEPT
    reason: Agrees with multiple IDA/EXP nuclear localization annotations.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic centrosome localization, corroborated by direct evidence that TRIP4 colocalizes with NEK6 at the centrosome. A specialized, context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Centrosomal localization is experimentally documented (NEK6 colocalization) but is peripheral to TRIP4's core transcriptional and RQC functions.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Colocalizes with NEK6 in the  centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Cytosolic localization is supported experimentally (PMID:10454579) and is the compartment for TRIP4's ribosome-quality-control role.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: TRIP4 has a C4-type zinc finger that binds zinc and mediates its protein interactions (with nuclear receptors, coactivators and UFSP2).
    action: ACCEPT
    reason: Zinc binding by the C4-type zinc finger is a structural molecular function underlying TRIP4's interaction surface; supported by domain annotation.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: The C4-type zinc finger mediates a competitive interaction with UFSP2 and ligand-bound nuclear receptors.
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation of rescue of stalled cytosolic ribosome, strongly corroborated by experimental evidence for the ASC-1/RQT complex.
    action: ACCEPT
    reason: Agrees with multiple IDA studies; a core biological process of TRIP4.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0180022
    label: RQC-trigger complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based electronic annotation of RQC-trigger complex membership, corroborated experimentally.
    action: ACCEPT
    reason: Agrees with IDA/IBA RQT-complex annotations; core cellular component.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4
- term:
    id: GO:0045661
    label: regulation of myoblast differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic (mouse ortholog) annotation of regulation of myoblast differentiation; TRIP4 is implicated in late myogenic differentiation and its loss causes congenital muscle disease.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: May play a role in late myogenic  differentiation
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) nucleoplasmic localization, consistent with TRIP4's nuclear coactivator role.
    action: ACCEPT
    reason: Agrees with experimental nuclear localization; appropriate cellular component for the transcriptional function.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) localization to nuclear bodies, a sub-nuclear compartment consistent with the nuclear coactivator function.
    action: KEEP_AS_NON_CORE
    reason: A genuine sub-nuclear localization from imaging, but more granular than needed for TRIP4's core function; retained as non-core.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948291
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (RQC pathway), consistent with the site of the ASC-1/RQT complex action on collided ribosomes.
    action: ACCEPT
    reason: Cytosol is the compartment where TRIP4 acts in ribosome-associated quality control; agrees with experimental localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948300
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (RQC pathway), redundant with the other cytosol annotations.
    action: ACCEPT
    reason: Consistent with TRIP4's cytosolic ribosome-quality-control site of action.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: NAS
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    summary: The ASC-1/RQT complex disassembles collided ribosomes; ribosome disassembly captures the splitting of the stalled (disome) ribosome by the complex.
    action: ACCEPT
    reason: Directly supported by experimental work (PMID:32579943, PMID:36302773) showing the ASC-1/RQT complex drives ribosomal subunit dissociation of collided ribosomes.
    supported_by:
    - reference_id: PMID:32579943
      supporting_text: disassembly of collided ribosomes.
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: The RQT complex recognizes ubiquitinated collided ribosomes to initiate RQC, leading to ubiquitin-dependent degradation of the nascent chain; well supported.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:20873783
  qualifier: located_in
  review:
    summary: Experimental nuclear localization, consistent with TRIP4's coactivator role.
    action: ACCEPT
    reason: Direct experimental support for nuclear localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:32579943
  qualifier: involved_in
  review:
    summary: Direct evidence that the ASC-1 complex disassembles collided ribosomes, the central mechanistic step of TRIP4's RQC function.
    action: ACCEPT
    reason: Directly demonstrated experimentally; core process of the ASC-1/RQT complex.
    supported_by:
    - reference_id: PMID:32579943
      supporting_text: disassembly of collided ribosomes.
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: involved_in
  review:
    summary: Direct evidence that the hRQT/ASC-1 complex mediates ribosomal subunit dissociation of ubiquitinated collided ribosomes.
    action: ACCEPT
    reason: Directly demonstrated experimentally; core process.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:32579943
  qualifier: involved_in
  review:
    summary: Direct evidence that the ASC-1 complex resolves collided ribosomes, rescuing stalled ribosomes via disassembly.
    action: ACCEPT
    reason: Directly demonstrated; core process of TRIP4's ribosome-quality-control role.
    supported_by:
    - reference_id: PMID:32579943
      supporting_text: disassembly of collided ribosomes.
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: involved_in
  review:
    summary: Direct evidence (disome collision study) that the hRQT/ASC-1 complex initiates rescue of collided ribosomes by subunit dissociation.
    action: ACCEPT
    reason: Directly demonstrated; core process.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IMP
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    summary: Mutational/functional evidence that TRIP4 within the RQT complex is required for ribosome-associated quality control of stalled ribosomes.
    action: ACCEPT
    reason: Supported by the identification and functional characterization of the RQT complex in mammalian RQC.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    summary: Functional evidence that TRIP4/RQT participates in ubiquitin-dependent degradation of nascent chains during RQC.
    action: ACCEPT
    reason: Supported by RQT-complex characterization in mammalian RQC.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:20873783
  qualifier: colocalizes_with
  review:
    summary: Direct evidence that TRIP4 colocalizes with NEK6 at the centrosome, a specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Genuine colocalization (NEK6 interactome study) but peripheral to TRIP4's core transcriptional and RQC functions.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Colocalizes with NEK6 in the  centrosome
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:20873783
  qualifier: enables
  review:
    summary: Interaction with the protein kinase NEK6 (Q9HC98), which phosphorylates TRIP4. A real but auxiliary binding function.
    action: KEEP_AS_NON_CORE
    reason: Documented NEK6 interaction (TRIP4 is phosphorylated by NEK6), informative but not a core molecular function of TRIP4.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with  NEK6
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:20873783
  qualifier: part_of
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3
- term:
    id: GO:0045661
    label: regulation of myoblast differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based annotation of regulation of myoblast differentiation, consistent with the muscle-disease phenotype but downstream of TRIP4's core functions.
    action: KEEP_AS_NON_CORE
    reason: Plausible role inferred from the ortholog and the congenital muscle phenotype, but not a core molecular function.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: May play a role in late myogenic  differentiation
- term:
    id: GO:0180022
    label: RQC-trigger complex
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: Directly demonstrated complex membership; the ASC-1 complex is the RQT complex, a core cellular component.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Directly demonstrated transcriptional regulatory activity; consistent with the coactivator core function.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: stimulates transactivation by serum response factor  (SRF), activating protein 1 (AP-1), and nuclear factor kappaB (NF-kappaB)
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:26924529
  qualifier: involved_in
  review:
    summary: Functional/disease evidence linking ASC-1 complex function to transcriptional regulation; consistent with the coactivator role.
    action: ACCEPT
    reason: Supports TRIP4's role in transcriptional regulation, demonstrated in the context of ASC-1-complex disease mutations.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Transcription coactivator which associates with nuclear
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: located_in
  review:
    summary: Direct nuclear localization, consistent with the coactivator role.
    action: ACCEPT
    reason: Direct experimental support for nuclear localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26924529
  qualifier: located_in
  review:
    summary: Direct nuclear localization, consistent with the coactivator role.
    action: ACCEPT
    reason: Direct experimental support for nuclear localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IMP
  original_reference_id: PMID:26924529
  qualifier: located_in
  review:
    summary: TRIP4 is implicated in neuromuscular junction development; a specialized, tissue-context localization tied to the disease phenotype.
    action: KEEP_AS_NON_CORE
    reason: Supported in the disease/neuromuscular context but peripheral to TRIP4's core molecular functions; a may-play-a-role statement.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: May play a role in the development of neuro
- term:
    id: GO:0030520
    label: estrogen receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIP4/ASC1 is required for ERalpha transactivation (via ufmylation), placing it in estrogen receptor signaling.
    action: ACCEPT
    reason: Directly demonstrated involvement in ERalpha-mediated transactivation.
    supported_by:
    - reference_id: PMID:25219498
      supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: TRIP4/ASC1 acts as a transcription coactivator whose ufmylation-dependent assembly of an EP300/NCOA1 coactivator complex potentiates nuclear-receptor transcription.
    action: ACCEPT
    reason: Directly demonstrated coactivator activity; a core molecular function.
    supported_by:
    - reference_id: PMID:25219498
      supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: TRIP4 positively regulates transcription, demonstrated through its requirement for ERalpha transactivation.
    action: ACCEPT
    reason: Directly demonstrated positive transcriptional regulation.
    supported_by:
    - reference_id: PMID:25219498
      supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: IntAct interactions (e.g. with DDRGK1, Q15788) from the ASC1-ufmylation study. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions but bare protein binding is uninformative; specific binding functions (nuclear-receptor, HAT, UFM1-ligase binding) are captured separately.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with DDRGK1 and UFL1; the interaction with  DDRGK1 is direct
- term:
    id: GO:0030331
    label: nuclear estrogen receptor binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: TRIP4 binds the ligand-bound nuclear estrogen receptor ESR1 (P03372), a specific and functionally central interaction for its coactivator role.
    action: ACCEPT
    reason: Directly documented binding to ESR1; an informative molecular function underlying TRIP4's estrogen-receptor coactivation.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with ESR1 (estrogen  ligand-bound); competes with UFSP2
- term:
    id: GO:0035035
    label: histone acetyltransferase binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: TRIP4 binds the histone acetyltransferase EP300/CBP (Q09472), recruited to assemble the active coactivator complex.
    action: ACCEPT
    reason: Directly documented EP300 interaction; an informative molecular function supporting the coactivator role.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with EP300
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: TRIP4 binds the UFM1-specific protease UFSP2 (Q9NUQ7); ligand-bound nuclear receptors compete with UFSP2 for TRIP4, regulating its ufmylation.
    action: ACCEPT
    reason: Directly documented UFSP2 interaction; an informative and mechanistically central binding function (governs the ufmylation switch).
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with UFSP2; competes with ligand-bound ESR1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: located_in
  review:
    summary: Direct nuclear localization in the ufmylation/ERalpha study.
    action: ACCEPT
    reason: Direct experimental support for nuclear localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0044389
    label: ubiquitin-like protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: TRIP4 binds the UFM1 E3 ligase component UFL1 (O94874) (and directly DDRGK1), consistent with TRIP4 being a ufmylation substrate.
    action: ACCEPT
    reason: Directly documented interaction with the UFM1 ligase machinery (UFL1/DDRGK1); an informative binding function central to TRIP4 ufmylation.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Interacts with DDRGK1 and UFL1; the interaction with  DDRGK1 is direct
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10454579
  qualifier: located_in
  review:
    summary: Direct nuclear localization in the original ASC-1 coactivator paper.
    action: ACCEPT
    reason: Direct experimental support for nuclear localization.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10454579
  qualifier: located_in
  review:
    summary: Direct cytoplasmic localization (under serum deprivation), consistent with the cytosolic pool where TRIP4 acts in RQC.
    action: ACCEPT
    reason: Experimentally supported; TRIP4 relocalizes to the cytoplasm under serum deprivation, and the RQC role is cytosolic.
    supported_by:
    - reference_id: file:human/TRIP4/TRIP4-uniprot.txt
      supporting_text: Cytoplasmic under conditions of  serum deprivation
- term:
    id: GO:0016922
    label: nuclear receptor binding
  evidence_type: IDA
  original_reference_id: PMID:10454579
  qualifier: enables
  review:
    summary: TRIP4 binds nuclear receptors (thyroid hormone receptor, estrogen receptor, androgen receptor) via its zinc-finger transactivation domain; central to its coactivator function.
    action: ACCEPT
    reason: Directly documented nuclear-receptor binding; a core molecular function underlying TRIP4's coactivator activity.
    supported_by:
    - reference_id: PMID:10454579
      supporting_text: nuclear receptors, as  demonstrated by the glutathione S-transferase pull-down assays and the yeast  two-hybrid tests.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10454579
  title: Activating signal cointegrator 1, a novel transcription coactivator of nuclear receptors, and its cytosolic localization under conditions of serum deprivation.
  findings:
  - statement: ASC-1 harbors a zinc-finger transactivation domain that binds basal transcription factors (TBP, TFIIA), coactivators (SRC-1, CBP/p300) and nuclear receptors; it is nuclear but cytoplasmic under serum deprivation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; seminal paper establishing TRIP4/ASC-1 as a nuclear-receptor transcription coactivator/cointegrator (GO:0003713), one of its two core functions.
- id: PMID:12077347
  title: Novel transcription coactivator complex containing activating signal cointegrator 1.
  findings:
  - statement: ASC-1 exists as a steady-state complex (with P200/ASCC3, P100/ASCC2, P50/ASCC1) and stimulates transactivation by SRF, AP-1 and NF-kappaB and relieves nuclear-receptor transrepression.
    reference_section_type: ABSTRACT
- id: PMID:20873783
  title: Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome.
  findings:
  - statement: TRIP4 interacts with the kinase NEK6 and colocalizes with NEK6 at the centrosome.
    reference_section_type: RESULTS
- id: PMID:25219498
  title: Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.
  findings:
  - statement: Ufmylation of ASC1/TRIP4 (promoted when ligand-bound ERalpha displaces the protease UFSP2) is required for ERalpha transactivation and assembly of an EP300/NCOA1 coactivator complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; supports the UFM1-regulated ERalpha coactivator function of TRIP4/ASC-1 (corroborates the transcription-coactivator core function and its regulation).
- id: PMID:26924529
  title: Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures.
  findings:
  - statement: Biallelic TRIP4 (and ASCC1) variants in the ASC-1 complex cause prenatal spinal muscular atrophy with congenital bone fractures; TRIP4 is implicated in neuromuscular junction development.
    reference_section_type: ABSTRACT
- id: PMID:32099016
  title: Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.
  findings:
  - statement: TRIP4/ASCC2/ASCC3 form the RQC-trigger (RQT) complex that facilitates ribosome-associated quality control in mammalian cells.
    reference_section_type: ABSTRACT
- id: PMID:32579943
  title: The ASC-1 Complex Disassembles Collided Ribosomes.
  findings:
  - statement: The ASC-1 complex disassembles collided ribosomes, the key mechanistic step initiating ribosome-associated quality control.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; establishes the RQC-trigger (RQT) function of the ASC-1/TRIP4 complex in disassembling collided ribosomes, the second core function of TRIP4.
- id: PMID:36302773
  title: A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation.
  findings:
  - statement: K63-linked polyubiquitination of uS10 at the disome collision interface triggers hRQT/ASC-1-mediated ribosomal subunit dissociation, initiating the RQC pathway.
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-9948291
  title: Reactome RQC pathway (cytosol localization of ASC-1/RQT complex)
  findings: []
- id: Reactome:R-HSA-9948300
  title: Reactome RQC pathway (cytosol localization of ASC-1/RQT complex)
  findings: []
core_functions:
- description: Subunit of the ASC-1 / RQC-trigger (RQT) complex that resolves collided ribosomes during ribosome-associated quality control, recognizing K63-polyubiquitinated disomes and driving ribosomal subunit dissociation to rescue stalled ribosomes and initiate nascent-chain degradation.
  in_complex:
    id: GO:0180022
    label: RQC-trigger complex
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:32579943
    supporting_text: disassembly of collided ribosomes.
  - reference_id: PMID:36302773
    supporting_text: the RQC-Trigger (RQT) complex recognizes ubiquitinated collided ribosomes as a substrate to initiate the RQC pathway by ribosomal subunit dissociation.
  directly_involved_in:
  - id: GO:0072344
    label: rescue of stalled cytosolic ribosome
- description: Nuclear transcriptional coactivator/cointegrator that, via its C4-type zinc-finger transactivation domain, binds nuclear receptors (thyroid hormone, estrogen ESR1, androgen receptors), basal transcription factors and coactivators (SRC-1/NCOA1, CBP/EP300) to potentiate nuclear-receptor-, SRF-, AP-1- and NF-kappaB-mediated transcription; regulated by UFM1 modification.
  molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:10454579
    supporting_text: nuclear receptors, as  demonstrated by the glutathione S-transferase pull-down assays and the yeast  two-hybrid tests.
  - reference_id: PMID:25219498
    supporting_text: ASC1 is a key step for ERα transactivation in  response to 17β-estradiol (E2).
proposed_new_terms: []
suggested_questions:
- question: 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)?
- question: Within the RQT complex, what is TRIP4's specific mechanistic contribution to recognizing K63-ubiquitinated collided ribosomes versus the ASCC3 helicase-driven splitting step?
- question: Are the congenital neuromuscular phenotypes of TRIP4 loss caused primarily by defective RQC, defective transcriptional coactivation, or both?
suggested_experiments:
- description: 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.
- description: 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.
- description: 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.