id: Q9UBS8
gene_symbol: RNF14
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RNF14 (E3 ubiquitin-protein ligase RNF14; legacy name ARA54, androgen
  receptor-associated protein 54) is a cytosolic, ribosome-associated
  RING-in-between-RING (RBR)-type E3 ubiquitin ligase (EC 2.3.2.31). It contains
  an N-terminal RWD domain and a C-terminal TRIAD/RBR module (RING1, IBR,
  atypical RING2) and works with E2 enzymes of the UBE2D/UBE2E families. Its
  principal characterized function is in the RNF14-RNF25 translational
  quality-control pathway acting on stalled and collided ribosomes. Recruited to
  stalled ribosomes by the ribosome-collision sensor GCN1, RNF14 catalyzes
  atypical Lys-6 (K6)-linked ubiquitination of translation factors eEF1A
  (EEF1A1) and eRF1 (ETF1) and of ribosomal proteins, marking them for
  proteasomal degradation. It is specifically required to resolve
  reactive-aldehyde (e.g. formaldehyde)-induced RNA-protein crosslinks that
  stall ribosomes, by K6-ubiquitinating the crosslinked species for extraction
  by the VCP/p97 unfoldase and subsequent degradation. Independently of this
  co-translational surveillance role, RNF14 also acts in the nucleus as a
  transcriptional coregulator. It promotes Wnt/TCF-beta-catenin-mediated
  transcription via interaction with TCF7/TCF7L1/TCF7L2, and acts as a
  coactivator for androgen- (and to a lesser extent progesterone-) dependent
  transcription via interaction with the androgen receptor. It is widely
  expressed and undergoes RING-dependent autoubiquitination.
existing_annotations:
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: As an RBR-type E3 ligase, RNF14 binds E2 ubiquitin-conjugating enzymes (UBE2E1/UBE2E2 experimentally; UBE2D family via interactome). E2 binding is mechanistically required for its ligase activity.
    action: ACCEPT
    reason: Directly supported by documented interaction with the E2 enzymes UBE2E1/UBE2E2 and consistent with the RBR catalytic mechanism (E2 binds RING1, trans-thiolation to the RING2 active-site cysteine). This supports, but is subordinate to, the core ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Interacts with the ubiquitin-conjugating enzymes UBE2E1 and UBE2E2
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: RNF14 functions as the catalytic E3 within the RNF14-RNF25 ubiquitin ligase machinery that acts on stalled ribosomes, consistent with being part of a ubiquitin ligase complex.
    action: ACCEPT
    reason: RNF14 is an E3 ligase that operates in concert with RNF25 and GCN1 on stalled ribosomes; the ubiquitin ligase complex localization is appropriate.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: General ubiquitin-protein transferase activity, the parent molecular function for RNF14's RBR E3 ligase catalysis.
    action: MODIFY
    reason: This generic transferase term is correct but less precise than the experimentally established ubiquitin protein ligase activity (GO:0061630). Generalize/replace with the specific ligase activity term that is supported by IDA evidence.
    proposed_replacement_terms:
    - id: GO:0061630
      label: ubiquitin protein ligase activity
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization is documented and is associated with RNF14's transcriptional coregulator (Wnt/TCF and androgen-receptor) moonlighting roles.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is genuine but tied to the transcriptional/AR/Wnt moonlighting functions rather than the core cytosolic ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:9853615}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is the compartment in which RNF14 acts on stalled ribosomes.
    action: ACCEPT
    reason: Cytoplasmic localization is experimentally documented and is where the core RNF14-RNF25 ribosome-associated ligase function takes place.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: RNF14 coordinates multiple zinc ions through its RING1, IBR and atypical RING2 zinc fingers, which are structural for the RBR module.
    action: KEEP_AS_NON_CORE
    reason: Zinc binding is a structural feature of the RBR zinc fingers; it is a true molecular property but is supportive/structural rather than the informative catalytic function.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Protein ubiquitination is the biological process carried out by RNF14's ligase activity.
    action: ACCEPT
    reason: RNF14 mediates ubiquitination of translation factors and ribosomal proteins; the protein ubiquitination process term is correct, though the K6-linked subtype is more specific.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: RNF14 regulates Wnt/TCF-beta-catenin-mediated transcription through interaction with TCF transcription factors, a moonlighting role independent of its ribosome surveillance function.
    action: KEEP_AS_NON_CORE
    reason: Supported by interaction with TCF7/TCF7L1/TCF7L2 and a documented role in colon cancer cell survival, but this is a secondary nuclear/transcriptional function distinct from the core ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: acts as a regulator of transcription in Wnt signaling via its interaction with TCF transcription factors
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Ubiquitin protein ligase activity is the core molecular function of RNF14, independently established by multiple experimental studies.
    action: ACCEPT
    reason: This is RNF14's defining molecular function (RBR-type E3 ligase, EC 2.3.2.31), corroborated by IDA evidence and active-site mutagenesis (Cys-220, Cys-417).
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19345326
  qualifier: enables
  review:
    summary: Interaction with the androgen receptor (AR, P10275) captured as bare protein binding. This underlies RNF14/ARA54's AR-coregulator role but the generic term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The AR interaction is real and biologically meaningful for the AR-coactivator moonlighting role, but bare protein binding is uninformative; the AR-specific function is better captured by the dedicated nuclear androgen receptor binding annotation.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Interacts with AR/androgen receptor
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: High-throughput E2 interactome screen capturing interactions with the ubiquitin-conjugating enzymes UBE2D1 (P51668) and UBE2D4 (Q9Y2X8).
    action: KEEP_AS_NON_CORE
    reason: The interaction partners are E2 enzymes, consistent with RNF14's RBR ligase mechanism, but bare protein binding is uninformative and the E2-binding function is already captured by ubiquitin conjugating enzyme binding.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:P51668
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale yeast two-hybrid interactome capturing RNF14 interactions (UBE2D1, DACH1, UBE2D4). Bare protein binding from a high-throughput screen.
    action: KEEP_AS_NON_CORE
    reason: Records genuine interactions but bare protein binding is uninformative and does not define a specific function for this gene.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:Q9UI36-2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Variant interactome screen capturing an RNF14-UBE2D4 (Q9Y2X8) interaction.
    action: KEEP_AS_NON_CORE
    reason: An E2-enzyme interaction consistent with RNF14's ligase mechanism; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:Q9Y2X8
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI interactome screen capturing an RNF14-DACH1 (Q9UI36-2) interaction.
    action: KEEP_AS_NON_CORE
    reason: Isolated high-throughput interaction; bare protein binding is uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:Q9UI36-2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen capturing interactions with PRKN/Parkin (O60260-5), GRN (P28799), TARDBP (Q13148) and RNF11 (Q9Y3C5).
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions with disease-related proteins; bare protein binding is uninformative and these partners do not define RNF14's core function.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:O60260-5
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) nucleoplasmic localization, consistent with RNF14's nuclear transcriptional moonlighting role.
    action: KEEP_AS_NON_CORE
    reason: Genuine localization tied to the nuclear transcriptional/AR/Wnt functions rather than the core cytosolic ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: GO:0005654; C:nucleoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) cytosolic localization, the compartment where RNF14 acts on stalled ribosomes.
    action: ACCEPT
    reason: Cytosolic localization corresponds to the core ribosome-associated ligase function and is supported by direct evidence.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: GO:0005829; C:cytosol
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: is_active_in
  review:
    summary: RNF14 is active at the cytosolic ribosome, where it ubiquitinates translation factors and ribosomal proteins on stalled ribosomes.
    action: ACCEPT
    reason: Directly supported by the GCN1-dependent recruitment of RNF14 to stalled ribosomes and ubiquitination of ribosomal proteins; this is the core site of action.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Recruited to stalled ribosomes by the ribosome collision sensor GCN1
- term:
    id: GO:0160127
    label: protein-RNA covalent cross-linking repair
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: RNF14 K6-ubiquitinates reactive-aldehyde-induced RNA-protein crosslinks that stall ribosomes, marking them for VCP-dependent extraction and resolution.
    action: ACCEPT
    reason: Directly demonstrated; RNF14 is specifically required to resolve formaldehyde-induced RNA-protein crosslinks.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Specifically required to resolve RNA-protein cross-links caused by reactive aldehydes
- term:
    id: GO:0160127
    label: protein-RNA covalent cross-linking repair
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: Independent study showing RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
    action: ACCEPT
    reason: Corroborated by a second independent study demonstrating RNF14's role in resolving RNA-protein crosslinks.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Specifically required to resolve RNA-protein cross-links caused by reactive aldehydes
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: enables
  review:
    summary: Direct demonstration of RNF14 E3 ligase catalytic activity, with Cys-220 active-site mutagenesis, in the eRF1-degradation branch of ribosome quality control.
    action: ACCEPT
    reason: Core molecular function established by IDA with catalytic-cysteine mutagenesis.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: enables
  review:
    summary: Direct demonstration that RNF14 (RBR E3 ligase) catalyzes atypical K6-linked ubiquitylation of formaldehyde-induced crosslinks.
    action: ACCEPT
    reason: Core molecular function established by direct biochemical evidence.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: enables
  review:
    summary: Independent direct demonstration of RNF14-dependent atypical ubiquitylation activity in RNA-protein crosslink resolution.
    action: ACCEPT
    reason: Core molecular function corroborated by a second independent study.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: involved_in
  review:
    summary: RNF14 participates in resolving stalled ribosomes by ubiquitinating and degrading translation factors (eRF1/eEF1A) on them.
    action: ACCEPT
    reason: Core biological-process role; RNF14 is required for the translational stress response to stalled ribosomes.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: RNF14 resolves stalled ribosomes caused by RNA-protein crosslinks via K6 ubiquitination and VCP extraction.
    action: ACCEPT
    reason: Core biological-process role supported by direct evidence in the crosslink-resolution context.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: which trigger translation stress by stalling ribosomes
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: Independent demonstration of RNF14's role in translation-coupled resolution of stalled ribosomes.
    action: ACCEPT
    reason: Core biological-process role corroborated by a second independent study.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: which trigger translation stress by stalling ribosomes
- term:
    id: GO:0085020
    label: protein K6-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: RNF14 catalyzes atypical Lys-6 (K6)-linked ubiquitination, the signature ubiquitin-chain type it produces on stalled-ribosome substrates and crosslinks.
    action: ACCEPT
    reason: Core, mechanistically distinctive activity directly demonstrated; K6-linked ubiquitylation marks formaldehyde-induced crosslinks for resolution.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: mediates 'Lys-6'-linked ubiquitination of target proteins
- term:
    id: GO:0085020
    label: protein K6-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: Independent demonstration of RNF14-mediated K6-linked ubiquitination.
    action: ACCEPT
    reason: Core distinctive activity corroborated by a second independent study.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: mediates 'Lys-6'-linked ubiquitination of target proteins
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:23449499
  qualifier: involved_in
  review:
    summary: RNF14 regulates TCF/beta-catenin-mediated (canonical Wnt) transcription and colon cancer cell survival via interaction with TCF transcription factors.
    action: KEEP_AS_NON_CORE
    reason: A genuine, experimentally supported nuclear transcriptional role, but a moonlighting function distinct from the core cytosolic ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: acts as a regulator of transcription in Wnt signaling via its interaction with TCF transcription factors
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF14-mediated ubiquitination targets substrates (stalled-ribosome translation factors and crosslinks) for proteasomal degradation.
    action: ACCEPT
    reason: The ubiquitin-dependent catabolic outcome of RNF14's ligase activity is directly supported; substrates are degraded by the proteasome.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: leading to their degradation
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: involved_in
  review:
    summary: RNF14 promotes degradation of translation factors on stalled ribosomes, a ubiquitin-dependent catabolic process.
    action: ACCEPT
    reason: Directly supported; the GCN1-RNF14 pathway promotes degradation of eEF1A/eRF1 and ribosomal proteins.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: is_active_in
  review:
    summary: RNF14 is active at the cytosolic ribosome.
    action: ACCEPT
    reason: Consistent with the GCN1-dependent recruitment to stalled ribosomes; core site of action.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Recruited to stalled ribosomes by the ribosome collision sensor GCN1
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: enables
  review:
    summary: Direct demonstration of RNF14 ubiquitin protein ligase activity.
    action: ACCEPT
    reason: Core molecular function established by direct evidence.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: enables
  review:
    summary: Direct demonstration of RNF14 catalytic ligase activity with Cys-417 active-site mutagenesis in the GCN1-engaged stalled-ribosome pathway.
    action: ACCEPT
    reason: Core molecular function established by IDA with catalytic-cysteine mutagenesis.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF14 participates in the response to stalled ribosomes.
    action: ACCEPT
    reason: Core biological-process role supported by direct evidence.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: involved_in
  review:
    summary: RNF14, engaged by GCN1, acts to resolve stalled ribosomes by degrading translation factors.
    action: ACCEPT
    reason: Core biological-process role; foundational study defining the GCN1-RNF14-RNF25 pathway.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Recruited to stalled ribosomes by the ribosome collision sensor GCN1
- term:
    id: GO:0085020
    label: protein K6-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF14 catalyzes K6-linked ubiquitination.
    action: ACCEPT
    reason: Core distinctive activity supported by direct evidence.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: mediates 'Lys-6'-linked ubiquitination of target proteins
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:19345326
  qualifier: involved_in
  review:
    summary: RNF14/ARA54 functions as a transcriptional coregulator of androgen-receptor-dependent transcription.
    action: KEEP_AS_NON_CORE
    reason: A genuine but moonlighting transcriptional role tied to AR/Wnt coregulation, distinct from the core cytosolic ligase function.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: May also play a role as a coactivator for androgen-
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:19345326
  qualifier: involved_in
  review:
    summary: RNF14/ARA54 acts as a coactivator, positively regulating androgen-receptor-dependent transcription.
    action: KEEP_AS_NON_CORE
    reason: A coactivator (positive-regulation) role consistent with the AR moonlighting function; non-core relative to the ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: May also play a role as a coactivator for androgen-
- term:
    id: GO:0050681
    label: nuclear androgen receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19345326
  qualifier: enables
  review:
    summary: RNF14/ARA54 binds the androgen receptor, the molecular basis for its AR-coactivator role; the C-terminal region (residues 361-474) mediates this interaction.
    action: KEEP_AS_NON_CORE
    reason: A genuine, specific interaction underpinning the AR-coregulator moonlighting function; informative but non-core relative to the ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Interacts with AR/androgen receptor
- term:
    id: GO:0060765
    label: regulation of androgen receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:19345326
  qualifier: involved_in
  review:
    summary: RNF14/ARA54 modulates androgen-receptor signaling/transcriptional output.
    action: KEEP_AS_NON_CORE
    reason: Part of the AR-coregulator moonlighting role; genuine but non-core.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: coactivator for androgen-
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEP
  original_reference_id: PMID:11322894
  qualifier: involved_in
  review:
    summary: Early characterization of ARA54/RNF14 as a RING-finger protein undergoing E2-dependent (auto)ubiquitination.
    action: ACCEPT
    reason: Protein ubiquitination is consistent with RNF14's ligase function (including RING-dependent, UBE2E2-dependent autoubiquitination).
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10085091
  qualifier: enables
  review:
    summary: Original ARA54 study; interaction captured here is with O14933 (UBE2L6), a ubiquitin-conjugating enzyme. Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: An E2-related interaction consistent with the ligase mechanism, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-goa.tsv
      supporting_text: UniProtKB:O14933
- term:
    id: GO:0030521
    label: androgen receptor signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:11322894
  qualifier: involved_in
  review:
    summary: Non-traceable-author statement placing ARA54/RNF14 in the androgen-receptor signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the AR-coregulator moonlighting role; retained as non-core.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Interacts with AR/androgen receptor
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: TAS
  original_reference_id: PMID:10085091
  qualifier: enables
  review:
    summary: RNF14/ARA54 was originally described as a transcriptional coactivator for the androgen receptor.
    action: KEEP_AS_NON_CORE
    reason: A genuine moonlighting molecular function (coactivator) tied to AR-dependent transcription; non-core relative to the ribosome-associated ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: coactivator for androgen-
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11322894
  qualifier: located_in
  review:
    summary: Direct evidence of nuclear localization, consistent with the transcriptional moonlighting role.
    action: KEEP_AS_NON_CORE
    reason: Genuine localization associated with the nuclear/transcriptional functions rather than the core cytosolic ligase activity.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:9853615}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11322894
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization, the compartment of the core ribosome-associated ligase function.
    action: ACCEPT
    reason: Cytoplasmic localization supported by direct evidence and corresponds to RNF14's core site of action.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:10085091
  qualifier: involved_in
  review:
    summary: RNF14/ARA54 as a coregulator of RNA polymerase II-dependent (androgen-receptor) transcription.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the transcriptional coregulator moonlighting role; non-core.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: coactivator for androgen-
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:10085091
  qualifier: involved_in
  review:
    summary: Very generic signal transduction term from the original ARA54 study, reflecting its role in hormone-receptor signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: Signal transduction is too generic to be informative for this gene; the more specific androgen-receptor signaling annotations already capture the relevant role.
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: Interacts with AR/androgen receptor
- term:
    id: GO:0019787
    label: ubiquitin-like protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:11322894
  qualifier: enables
  review:
    summary: Early characterization of ARA54/RNF14 E2-dependent ubiquitin transfer activity, annotated with the broader ubiquitin-like transferase term.
    action: MODIFY
    reason: RNF14 transfers ubiquitin (not other UBLs); the broader ubiquitin-like protein transferase term should be replaced by the specific ubiquitin protein ligase activity established by later experimental work.
    proposed_replacement_terms:
    - id: GO:0061630
      label: ubiquitin protein ligase activity
    supported_by:
    - reference_id: file:human/RNF14/RNF14-uniprot.txt
      supporting_text: RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB keywords
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10085091
  title: Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor.
  findings:
  - statement: Identified ARA54 (RNF14) as an androgen-receptor-associated coactivator protein in prostate.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Original ARA54 cloning/AR-coactivator paper; not cached. Title from UniProt reference list. Supports the legacy AR-coregulator moonlighting role.
- id: PMID:11322894
  title: N-terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8.
  findings:
  - statement: ARA54/RNF14 interacts with UBE2E1/UBE2E2 and undergoes RING- and UBE2E2-dependent autoubiquitination; Cys-220 is required.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Title from UniProt reference list; not cached. Establishes E2 interaction and autoubiquitination consistent with RBR ligase mechanism.
- id: PMID:19345326
  title: Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination.
  findings:
  - statement: Characterizes RNF14/ARA54 interaction with and coregulation of the androgen receptor.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Title from UniProt reference list; not cached. Supports AR binding and AR-signaling regulation moonlighting role.
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: High-throughput interactome capturing RNF14-UBE2D1/UBE2D4; supports E2 binding only.
- id: PMID:23449499
  title: Ring Finger Protein 14 is a new regulator of TCF/beta-catenin-mediated transcription and colon cancer cell survival.
  findings:
  - statement: RNF14 interacts with TCF7/TCF7L1/TCF7L2 and promotes canonical Wnt/beta-catenin transcription and colon cancer cell survival.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Title from UniProt reference list; not cached. Establishes the Wnt/TCF transcriptional moonlighting role.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: HuRI Y2H interactome; bare protein-binding partners only.
- id: PMID:27863242
  title: Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes.
  findings:
  - statement: Context establishing ribosome-associated ubiquitylation and quality control in which RNF14 ligase activity acts.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Cached; RQC-context paper supporting ribosome-associated ubiquitin ligase/catabolic annotations.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Binary interactome screen; bare protein-binding partner (UBE2D4).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: High-throughput interactome; bare protein-binding partner (DACH1).
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Neurodegeneration interactome; bare protein-binding partners (PRKN/GRN/TARDBP/RNF11).
- id: PMID:36638793
  title: An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
  findings:
  - statement: GCN1 recruits RNF14 (with RNF25) to stalled ribosomes to ubiquitinate and degrade translation factors eEF1A and eRF1 and ribosomal proteins; Cys-417 is the active site.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; foundational paper defining the GCN1-RNF14-RNF25 stalled-ribosome pathway and RNF14 catalytic activity.
- id: PMID:37651229
  title: Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.
  findings:
  - statement: RNF14 (and RNF25), engaged by GCN1, catalyze eRF1 degradation as a branch of ribosome quality control; RNF14 Cys-220 is required.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; establishes RNF14 catalytic activity and the eRF1-degradation branch.
- id: PMID:37951215
  title: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.
  findings:
  - statement: RNF14 (RBR E3) catalyzes atypical K6-linked ubiquitylation of formaldehyde-induced RNA-protein crosslinks, which are then resolved by the VCP unfoldase.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; establishes K6-linked ubiquitination and RNA-protein crosslink resolution.
- id: PMID:37951216
  title: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
  findings:
  - statement: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; independent corroboration of RNF14's role in RNA-protein crosslink resolution.
core_functions:
- description: RING-in-between-RING (RBR)-type E3 ubiquitin-protein ligase that catalyzes atypical Lys-6 (K6)-linked ubiquitination of substrates on stalled/collided cytosolic ribosomes, working with E2 enzymes and in concert with RNF25 and the collision sensor GCN1.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/RNF14/RNF14-uniprot.txt
    supporting_text: E3 ubiquitin-protein ligase that plays a key role in the
  - reference_id: file:human/RNF14/RNF14-uniprot.txt
    supporting_text: mediates 'Lys-6'-linked ubiquitination of target proteins
- description: Acts in ribosome-associated translational quality control by ubiquitinating and promoting degradation of translation factors (eEF1A, eRF1) and ribosomal proteins on stalled ribosomes, and by resolving reactive-aldehyde-induced RNA-protein crosslinks for VCP-dependent extraction and proteasomal degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/RNF14/RNF14-uniprot.txt
    supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
  - reference_id: file:human/RNF14/RNF14-uniprot.txt
    supporting_text: Specifically required to resolve RNA-protein cross-links caused by reactive aldehydes
proposed_new_terms: []
suggested_questions:
- question: What determines RNF14 substrate selection (eEF1A vs eRF1 vs ribosomal proteins vs RNA-protein crosslinks) on stalled ribosomes, and how is this coordinated with RNF25?
- question: Is the nuclear transcriptional coregulator role (AR/Wnt) mechanistically dependent on RNF14 ligase activity, or is it a ligase-independent scaffolding function?
- question: How is the choice of K6-linked chain topology achieved by the atypical RBR module that lacks the canonical RING2 histidine?
suggested_experiments:
- description: Ribosome profiling and quantitative ubiquitin-site proteomics in RNF14 and RNF14/RNF25 double knockouts after formaldehyde or stalling stress to map the full K6-ubiquitinated substrate set.
- description: Structure-function analysis (cryo-EM of RNF14-GCN1-stalled ribosome complexes) to define how GCN1 recruits and positions RNF14 on collided ribosomes.
- description: Separation-of-function mutants (catalytic-dead Cys-417/Cys-220 vs AR/TCF-binding-deficient C-terminal mutants) to test whether the transcriptional moonlighting roles require ligase activity.