id: Q99942
gene_symbol: RNF5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RNF5 (RMA1, NG2/G16) is a small (180 aa) tail-anchored RING-type E3
  ubiquitin-protein ligase (EC 2.3.2.27) embedded in the endoplasmic reticulum
  membrane via two C-terminal transmembrane helices, with an N-terminal
  cytosolic C3HC4 RING domain (catalytic Cys-42) that recruits ubiquitin-charged
  E2 enzymes (notably the UBE2D/UbcH5 family and UBE2N/Ubc13). RNF5 is one of
  the founding mammalian ER-anchored ERAD ubiquitin ligases. Together with the
  E2 UBE2J1/Ubc6e and Derlin-1 it recognizes folding defects in membrane
  proteins co-translationally and assembles K48-linked polyubiquitin chains that
  commit misfolded clients such as CFTR and the disease-associated CFTR-deltaF508
  mutant to retrotranslocation and proteasomal degradation; it functions partly
  redundantly with its close paralog RNF185, with which it forms an E3 ligase
  module central to CFTR degradation. Beyond canonical ERAD, RNF5 has documented
  ligase-dependent regulatory roles that use distinct chain topologies and
  substrates. It builds non-degradative K63-linked chains on the ERAD adaptor
  JKAMP/JAMP to limit its recruitment of proteasome and p97/VCP components; it
  ubiquitinates and degrades the innate-immune adaptor STING1/MITA at
  mitochondria to dampen antiviral type I interferon responses; it controls
  basal autophagy by regulating the stability of a membrane pool of the cysteine
  protease ATG4B; and it ubiquitinates paxillin to influence cell motility. RNF5
  is widely expressed, and although localized predominantly to membranes (with
  reported plasma-membrane and mitochondrial-membrane pools), its ER-membrane
  localization underlies its core ERAD ligase function.
existing_annotations:
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of RING-type ubiquitin ligase activity, the core molecular function of RNF5, conserved across the RNF5/RNF185 family.
    action: ACCEPT
    reason: Core molecular function; supported experimentally (EC 2.3.2.27; C42S abolishes activity) and across the family.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in ER-associated degradation, the core biological process of RNF5 as an ER-anchored ERAD ligase.
    action: ACCEPT
    reason: Core biological process; directly supported by IMP evidence (CFTR/CFTR-deltaF508 degradation) and conserved in the family.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: Cystic fibrosis transmembrane conductance regulator (CFTR) is one ERAD substrate targeted to co-translational degradation by the E3 ligase RNF5/RMA1
- term:
    id: GO:0044390
    label: ubiquitin-like protein conjugating enzyme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RNF5 binds ubiquitin-conjugating (E2) enzymes, including the UBE2D/UbcH5 family and UBE2N/Ubc13, as part of its catalytic cycle. This is informative but ancillary to the ligase activity itself.
    action: KEEP_AS_NON_CORE
    reason: Accurately reflects E2 binding (UBE2D1/UBE2D2, UBE2N) required for catalysis, but is a mechanistic subsidiary of the core ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: May function together with E2 ubiquitin-conjugating enzymes UBE2D1/UBCH5A and UBE2D2/UBC4
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based electronic assignment of ER localization, consistent with RNF5's ER-membrane site of ERAD function.
    action: ACCEPT
    reason: Correct compartment; redundant with the more specific ER membrane annotations and IDA (HPA) evidence.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439}'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; this is the core compartment for RNF5's ERAD ligase function.
    action: ACCEPT
    reason: Correct core localization; RNF5 is a tail-anchored ER membrane protein, supported experimentally (EXP, PMID:19285439).
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439}'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of plasma membrane localization from the original cloning study (PMID:9533025). A real but secondary localization not tied to the core ERAD function.
    action: KEEP_AS_NON_CORE
    reason: Reported in the early cloning paper but the functionally dominant compartment for RNF5 is the ER membrane; plasma membrane pool is peripheral.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Cell membrane {ECO:0000269|PubMed:9533025}'
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of ubiquitin-dependent protein catabolism, a parent process consistent with RNF5's ERAD role.
    action: ACCEPT
    reason: Correct but generic; the specific GO:0036503 (ERAD pathway) better captures the core biological role.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: degraded by the ubiquitin-proteasome pathway through a process called ER-associated degradation (ERAD)
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of mitochondrial membrane localization, reflecting the antiviral STING1/MITA study in which RNF5 acts at mitochondria. A real but secondary, immunity-related localization.
    action: KEEP_AS_NON_CORE
    reason: Supported by PMID:19285439 (MITA ubiquitination at mitochondria) but represents a secondary, context-specific role distinct from the core ER-membrane ERAD function.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning electronic assignment of the ERAD pathway, redundant with the experimentally supported core process.
    action: ACCEPT
    reason: Correct core biological process; redundant with IMP and IBA evidence.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: Cystic fibrosis transmembrane conductance regulator (CFTR) is one ERAD substrate targeted to co-translational degradation by the E3 ligase RNF5/RMA1
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: Inter-ontology logical inference placing RNF5 in the ER quality control compartment, a plausible localization derived from its ERAD role.
    action: KEEP_AS_NON_CORE
    reason: Plausible localization inferred from the ERAD/ERQC link, but not directly demonstrated; the core localization annotation is ER membrane.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: hosts a machinery called ERQC for ER quality control
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Combined automated electronic assignment of the core RING E3 ligase activity, consistent with EC 2.3.2.27 and experimental evidence.
    action: ACCEPT
    reason: Correct core molecular function; redundant with EXP/IBA evidence.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of ER mannose trimming. RNF5 is a ubiquitin ligase and does not trim mannose; this is a pathway-adjacency over-annotation propagated from the ERAD/ERQC context.
    action: REMOVE
    reason: RNF5 has no glycosidase/mannosidase activity; mannose trimming is performed by EDEM/ER mannosidases, not by the E3 ligase. This electronic inference is biologically incorrect.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12861019
  qualifier: enables
  review:
    summary: IntAct interaction with paxillin (PXN), a functionally meaningful RNF5 substrate, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real substrate interaction (PXN) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:12861019
      supporting_text: the human homologue of RNF5 associates with the amino-terminal domain of paxillin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14667819
  qualifier: enables
  review:
    summary: High-throughput yeast two-hybrid interactions (e.g. ABHD16A, UBE2 enzymes). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real IntAct interactions but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; O95870: ABHD16A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16901789
  qualifier: enables
  review:
    summary: Interaction with CFTR captured in the sequential-triage ERAD study; CFTR is a key RNF5 ERAD substrate. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important RNF5-CFTR interaction, but bare protein binding is uninformative; the substrate relationship is captured by the ERAD process annotations.
    supported_by:
    - reference_id: PMID:16901789
      supporting_text: an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1, the E2 Ubc6e, and Derlin-1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: E2 ubiquitin-conjugating enzyme interaction network capturing RNF5 binding to multiple UBE2D/UBE2E/UBE2W E2s. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real E2 interactions relevant to catalysis but bare protein binding is uninformative; E2 binding is captured by GO:0044390.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; P51668: UBE2D1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20152160
  qualifier: enables
  review:
    summary: Interaction with the E2 UBE2D2/UbcH5b from a structural study of the E2~Ub conjugate. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real E2 interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; P62837: UBE2D2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Large-scale interactome map capturing numerous RNF5 partners (including SLC transporters, RNF185, SEC22A). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q96GF1: RNF185'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25759021
  qualifier: enables
  review:
    summary: Interactions with glutamine carrier proteins (SLC1A5, SLC38A2) relevant to RNF5's role in breast cancer ER-stress response. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real substrate/carrier interactions but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q15758: SLC1A5'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26618866
  qualifier: enables
  review:
    summary: Interaction with CFTR from a deltaF508 CFTR interactome-remodeling study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real CFTR interaction relevant to ERAD but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; P13569: CFTR'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Interaction captured in a study of variant-driven interactome disruption. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q969T4: UBE2E3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map capturing many RNF5 membrane-protein partners. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q9Y5U4: INSIG2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Interactions (e.g. OPTN, UBE2K) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q96CV9: OPTN'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing RNF5 partners including RNF185 and RHBDD1. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q96GF1: RNF185'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  qualifier: enables
  review:
    summary: Proximity-labeling interaction with CFTR identifying enrichment in SLC transporters. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real CFTR/SLC interactions but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; P13569: CFTR'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: RNF5 self-interaction captured in a proteome-scale interactome. Reflects homo-association seen in screens.
    action: KEEP_AS_NON_CORE
    reason: Documents RNF5 self-association (IntAct EBI-348482 with itself) but is peripheral to the core ligase function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q99942: RNF5'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: RNF5 self-interaction captured in the binary interactome reference map.
    action: KEEP_AS_NON_CORE
    reason: Documents RNF5 self-association but is peripheral to the core ligase function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Q99942; Q99942: RNF5'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment of generic membrane localization, a parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the more specific ER membrane localization.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382556
  qualifier: involved_in
  review:
    summary: Reactome pathway-level annotation (ABC-family transport). RNF5 is a ubiquitin ligase, not a transporter; this reflects pathway context (CFTR/ABC transport) bleed-through.
    action: REMOVE
    reason: RNF5 does not mediate transmembrane transport; it is an E3 ligase acting on transporter substrates such as CFTR. The transport annotation is a pathway-adjacency artifact, not a direct function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein ubiquitination process, a parent of the specific ERAD-associated ubiquitination RNF5 performs.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific ERAD pathway and K48/K63 ubiquitination annotations better capture the role.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866546
  qualifier: enables
  review:
    summary: Reactome curation of RNF5 (with RNF185) ubiquitinating misfolded CFTR; captures the core ligase activity.
    action: ACCEPT
    reason: Correct core molecular function in the CFTR ERAD reaction.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  qualifier: enables
  review:
    summary: Reactome curation of the ERAD E3 ligase ubiquitinating an unfolded glycoprotein substrate; captures the core ligase activity.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with RNF5's ER-membrane ERAD function.
    action: ACCEPT
    reason: IDA-supported ER localization agrees with the documented ER-membrane site of action.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439}'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:19285439
  qualifier: located_in
  review:
    summary: Experimental evidence that RNF5 localizes to the ER membrane; the core compartment for its ERAD ligase activity.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:9533025
  qualifier: located_in
  review:
    summary: Experimental localization to the plasma membrane reported in the original cloning study. A real but secondary localization.
    action: KEEP_AS_NON_CORE
    reason: Documented in the cloning paper but the functionally dominant compartment is the ER membrane; plasma-membrane pool is peripheral to the core ERAD role.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: 'Predominantly located in the plasma membrane, with some localization occurring within cytoplasmic organelles'
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:19285439
  qualifier: located_in
  review:
    summary: Experimental localization to the mitochondrial membrane, where RNF5 ubiquitinates STING1/MITA during antiviral responses. A real but secondary, immunity-related localization.
    action: KEEP_AS_NON_CORE
    reason: Directly supported (PMID:19285439) but a secondary compartment for a context-specific immune role, not the core ER ERAD function.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:19269966
  qualifier: enables
  review:
    summary: Experimental demonstration of RNF5 ubiquitin ligase activity (RING-dependent ubiquitination of JAMP). Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; WT but not RING-mutant RNF5 ubiquitinates substrate.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: Ectopically expressed JAMP was efficiently ubiquitinated in vivo by WT but not the RING mutant form of RNF5
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:19285439
  qualifier: enables
  review:
    summary: Experimental demonstration of RNF5 ligase activity ubiquitinating STING1/MITA. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:23093945
  qualifier: enables
  review:
    summary: Experimental demonstration of RNF5 ligase activity controlling ATG4B ubiquitination and stability. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:23093945
      supporting_text: the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:24019521
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence (with RNF185) that RNF5 drives ubiquitin-dependent degradation of CFTR; redundant depletion blocks CFTR-deltaF508 turnover.
    action: ACCEPT
    reason: Supported by the RNF5/RNF185 co-depletion experiments; consistent with the core ERAD/proteasomal degradation role.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: simultaneous depletion of RNF5 and RNF185 profoundly blocks CFTRΔF508 degradation not only during translation but also after synthesis is complete
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:24019521
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that RNF5 is required for ERAD of CFTR/CFTR-deltaF508. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support from depletion experiments.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: simultaneous depletion of RNF5 and RNF185 profoundly blocks CFTRΔF508 degradation
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: Author statement of RNF5 ubiquitin ligase activity in CFTR ERAD. Core molecular function.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: targeted to co-translational degradation by the E3 ligase RNF5/RMA1
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  qualifier: involved_in
  review:
    summary: Reactome ERQC pathway annotation. RNF5 does not perform mannose trimming; this is pathway-adjacency over-annotation.
    action: REMOVE
    reason: RNF5 is an E3 ligase with no mannosidase activity; ER mannose trimming is carried out by ER mannosidases/EDEMs. The annotation conflates pathway membership with direct activity.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IPI
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: RNF5 binds a protein complex (ERAD machinery) in the CFTR degradation study. More informative than bare protein binding but still ancillary.
    action: KEEP_AS_NON_CORE
    reason: Reflects association with the ERAD E3 module/machinery; supportive of, but subsidiary to, the core ligase and ERAD-process annotations.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866542
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization within CFTR ERAD reactions. Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866546
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (RNF5/RNF185 ubiquitinate misfolded CFTR). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866551
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (CFTR binds ERAD machinery). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866854
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (CFTR F508del translocation). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866856
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (RNF5/RNF185 ubiquitinate CFTR F508del). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866857
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (CFTR F508del binds ERAD machinery). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization in an ERAD ubiquitination reaction. Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931264
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (CD274/PD-L1 ERAD transport). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931298
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (ubiquitination of CD274 by ERAD complex). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931313
  qualifier: located_in
  review:
    summary: Reactome curation of RNF5 ER membrane localization (p-CD274 binds ERAD complex). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: Interaction captured in the RNF185/RNF5 CFTR ERAD study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction within the ERAD module but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:19285439
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that RNF5 drives degradation of a target protein (STING1/MITA). A parent of the more specific ubiquitin-dependent catabolic/ERAD process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific ERAD and K48-ubiquitination annotations; here the catabolic target is the immune adaptor MITA.
    supported_by:
    - reference_id: PMID:19285439
      supporting_text: RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:19285439
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF5 builds K48-linked polyubiquitin chains (degradative topology) on STING1/MITA. This degradative topology is also used on CFTR.
    action: ACCEPT
    reason: Directly demonstrated K48-linked ubiquitination, the canonical degradative topology underlying RNF5's ERAD and MITA-degradation roles.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: CFTR ubiquitination occurred at the canonical Lys-48 topology
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:19269966
  qualifier: enables
  review:
    summary: Direct evidence of ubiquitin-protein transferase activity, a parent of the specific RING-type ubiquitin ligase activity.
    action: ACCEPT
    reason: Correct general molecular function; the specific GO:0061630 captures the RING E3 ligase activity.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: Ectopically expressed JAMP was efficiently ubiquitinated in vivo by WT but not the RING mutant form of RNF5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19269966
  qualifier: enables
  review:
    summary: Interaction with JKAMP/JAMP, a functionally important RNF5 substrate/partner at the ER membrane. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real RNF5-JAMP interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: RNF5 associates with JAMP in the ER membrane
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:19269966
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking RNF5 to ERAD, here via regulation of the ERAD adaptor JAMP. Core biological process.
    action: ACCEPT
    reason: Core biological process; RNF5 modulates ERAD both by direct substrate ubiquitination and by K63-regulation of JAMP.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:19269966
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF5 builds non-degradative K63-linked polyubiquitin chains on JAMP (Ubc13/UBE2N-dependent), a regulatory rather than degradative modification.
    action: ACCEPT
    reason: Directly demonstrated K63-linked ubiquitination, establishing RNF5's capacity for non-canonical regulatory ubiquitination distinct from K48 degradative chains.
    supported_by:
    - reference_id: PMID:19269966
      supporting_text: These findings establish that RNF5 mediates Lys-63-based polyubiquitination of JAMP
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: TAS
  original_reference_id: PMID:9533025
  qualifier: enables
  review:
    summary: The C3HC4 RING domain coordinates zinc as a structural requirement for the ligase fold. A structural attribute supporting, not equal to, the ligase activity.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural feature of the RING domain (residues 27-68) but subsidiary to the informative ubiquitin ligase activity; not a standalone core function.
    supported_by:
    - reference_id: file:human/RNF5/RNF5-uniprot.txt
      supporting_text: RING-type
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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:0000108
  title: Automatic assignment of GO terms using logical inference, based on inter-ontology links
  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:12861019
  title: RNF5, a RING finger protein that regulates cell motility by targeting paxillin ubiquitination and altered localization.
  findings:
  - statement: RNF5 associates with the N-terminal domain of paxillin and mediates its ubiquitination, requiring intact RING and C-terminal domains, regulating cell motility.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes a non-core cell-motility role via paxillin ubiquitination; the source of the GO:0005515 PXN interaction.
- id: PMID:14667819
  title: Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput Y2H interactome (MHC class III region); source of several bare protein binding annotations.
- id: PMID:16901789
  title: Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator.
  findings:
  - statement: An ER membrane-associated ubiquitin ligase complex of E3 RMA1/RNF5, E2 Ubc6e and Derlin-1 recognizes folding defects in CFTR/CFTR-deltaF508 co-translationally and cooperates with cytosolic Hsc70/CHIP to promote proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study establishing RNF5/RMA1 as a co-translational ER-membrane ERAD ligase for CFTR.
- id: PMID:19269966
  title: Regulation of endoplasmic reticulum-associated degradation by RNF5-dependent ubiquitination of JNK-associated membrane protein (JAMP).
  findings:
  - statement: RNF5 builds Ubc13(UBE2N)-dependent K63-linked polyubiquitin chains on the ERAD adaptor JAMP at the ER membrane, reducing JAMP association with proteasome subunits and p97/VCP and thereby limiting ERAD; RNF5 builds canonical K48 chains on CFTR.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; demonstrates RNF5 RING-dependent ligase activity and distinct K48 (CFTR) vs K63 (JAMP) chain topologies.
- id: PMID:19285439
  title: The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.
  findings:
  - statement: RNF5 interacts with STING1/MITA in a virus-infection-dependent manner and builds K48-linked chains on MITA at Lys150 for proteasomal degradation at mitochondria, negatively regulating type I interferon antiviral responses; RNF5 localizes at ER and mitochondria.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the non-core antiviral/immunity role and mitochondrial localization; source of K48 ubiquitination and mitochondrial-membrane annotations.
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: E2 interaction network; documents RNF5 binding to multiple UBE2D/UBE2E/UBE2W enzymes relevant to its catalytic cycle.
- id: PMID:20152160
  title: 'Crystal structure of UbcH5b~ubiquitin intermediate: insight into the formation of the self-assembled E2~Ub conjugates.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Structural E2~Ub study; captures RNF5-UBE2D2 interaction.
- id: PMID:23093945
  title: Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.
  findings:
  - statement: RNF5 regulates basal autophagy by controlling the stability of a membrane pool of the cysteine protease ATG4B, thereby limiting LC3/ATG8 processing required for autophagosome formation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the non-core autophagy-regulatory role via ATG4B; provides EXP support for ligase activity.
- id: PMID:24019521
  title: RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).
  findings:
  - statement: RNF185 and RNF5 form a partly redundant E3 ligase module central to CFTR/CFTR-deltaF508 degradation; co-depletion profoundly blocks CFTR-deltaF508 degradation during and after translation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes RNF5/RNF185 redundancy in CFTR ERAD; source of IMP/IGI ERAD annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of multiple bare protein binding and identical protein binding (self) annotations.
- id: PMID:25759021
  title: Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.
  findings:
  - statement: RNF5 regulates glutamine carrier proteins (SLC1A5, SLC38A2) under ER stress, influencing breast cancer response to chemotherapy.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Non-core cancer/ER-stress role; source of SLC transporter interactions.
- id: PMID:26618866
  title: ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: CFTR-deltaF508 interactome study; captures RNF5-CFTR interaction relevant to ERAD.
- 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: VERIFIED
    review_notes: High-throughput variant-interactome study; source of a bare protein binding annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of multiple bare protein binding and self-interaction annotations.
- 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: VERIFIED
    review_notes: Neurodegeneration interactome; source of bare protein binding annotations (e.g. OPTN, UBE2K).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of bare protein binding annotations (RNF185, RHBDD1).
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: CFTR proximity-labeling interactome; captures RNF5-CFTR interaction relevant to ERAD.
- id: PMID:9533025
  title: Cloning, expression and mapping of a novel RING-finger gene (RNF5), a human homologue of a putative zinc-finger gene from Caenorhabditis elegans.
  findings:
  - statement: Original cloning of RNF5, a RING-finger gene in the MHC class III region; reported widespread expression and predominantly plasma-membrane localization with some cytoplasmic-organelle localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original cloning/characterization; source of zinc ion binding (TAS) and plasma-membrane localization annotations.
- id: Reactome:R-HSA-382556
  title: ABC-family proteins mediated transport
  findings: []
- id: Reactome:R-HSA-8866542
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR into the cytosol
  findings: []
- id: Reactome:R-HSA-8866546
  title: RNF5 and RNF185 ubiquitinate misfolded CFTR
  findings: []
- id: Reactome:R-HSA-8866551
  title: CFTR binds components of the ERAD machinery for ubiquitination and degradation
  findings: []
- id: Reactome:R-HSA-8866854
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into the cytosol
  findings: []
- id: Reactome:R-HSA-8866856
  title: RNF5 and RNF185 ubiquitinate CFTR F508del
  findings: []
- id: Reactome:R-HSA-8866857
  title: CFTR F508del binds components of the ERAD machinery for ubiquitination and degradation
  findings: []
- id: Reactome:R-HSA-8867288
  title: OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitinates unfolded protein:(GlcNAc)2 (Man)9-5
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
- id: Reactome:R-HSA-9931264
  title: Active transport of ubiquitinated CD274 from ER to cytosol
  findings: []
- id: Reactome:R-HSA-9931298
  title: Ubiquitination of CD274 by ERAD complex
  findings: []
- id: Reactome:R-HSA-9931313
  title: p-S195-CD274 binds ERAD complex
  findings: []
- id: PMID:39098896
  title: RING finger protein 5 protects against acute myocardial infarction by inhibiting ASK1.
  findings:
  - statement: RNF5 is downregulated in infarcted heart tissue; RNF5 knockout worsens and RNF5 overexpression ameliorates myocardial infarction injury in mouse and cardiomyocyte models, with protection attributed to inhibition of ASK1 (MAP3K5) activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:39098896 = BMC Cardiovasc Disord 2024, DOI 10.1186/s12872-024-04070-z); proposes a non-core cardioprotective role for RNF5 via the ASK1 stress-signaling pathway. Directness of RNF5 E3 action on ASK1 not fully resolved; full text not in cache, so no supporting_text added to annotations.
core_functions:
- description: RING-type E3 ubiquitin ligase anchored in the ER membrane that ubiquitinates misfolded membrane-protein clients (e.g. CFTR and CFTR-deltaF508) with K48-linked chains to commit them to retrotranslocation and proteasomal degradation via the ERAD pathway, acting partly redundantly with RNF185.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:16901789
    supporting_text: an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1, the E2 Ubc6e, and Derlin-1
  - reference_id: PMID:24019521
    supporting_text: identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: ER-membrane ubiquitin ligase that builds non-degradative K63-linked polyubiquitin chains on the ERAD adaptor JKAMP/JAMP (UBE2N/Ubc13-dependent), modulating its recruitment of proteasome and p97/VCP components and thereby regulating ERAD flux.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:19269966
    supporting_text: These findings establish that RNF5 mediates Lys-63-based polyubiquitination of JAMP
  directly_involved_in:
  - id: GO:0070534
    label: protein K63-linked ubiquitination
proposed_new_terms: []
suggested_questions:
- question: What determines RNF5 substrate selectivity and chain-topology choice (K48 degradative on CFTR/MITA vs K63 regulatory on JAMP), and which E2 partner (UBE2D vs UBE2N) is decisive in each case?
- question: To what extent are RNF5's antiviral (STING1/MITA) and autophagy (ATG4B) roles separable from its core ER ERAD function, and do they require distinct subcellular pools?
suggested_experiments:
- description: Reconstitute ERAD ubiquitination of CFTR-deltaF508 in vitro with purified RNF5, RNF185, UBE2J1/Ubc6e and Derlin-1 to map lysine sites and ubiquitin-chain linkage on the substrate and to dissect RNF5/RNF185 redundancy.
- description: Generate RNF5 and RNF5/RNF185 double-knockout cells and perform quantitative ubiquitinome/proteome profiling under basal and ER-stress conditions to define the endogenous ERAD substrate repertoire and the degree of paralog redundancy.