id: Q96GF1
gene_symbol: RNF185
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RNF185 is a small (192 aa) membrane-anchored RING-type E3 ubiquitin-protein
  ligase (EC 2.3.2.27) and a close paralog of RNF5/RMA1 in the RNF5/RNF185-like
  family. It has a cytoplasmic N-terminal C3HC4 RING domain (catalytic Cys-39;
  the RING domain is responsible for ligase activity) and two C-terminal
  transmembrane helices that anchor it in membranes. RNF185 is an
  ER-membrane-resident ERAD ubiquitin ligase: it mediates the cotranslational
  ubiquitination and proteasomal degradation of the misfolded membrane protein
  CFTR (including CFTR-deltaF508), and it functions partly redundantly with RNF5
  as an E3 ligase module that is central to CFTR degradation. Its expression is
  induced by the unfolded protein response and ER stress, and it protects cells
  from ER stress-induced apoptosis; it preferentially partners with the
  ER-associated E2 enzymes UBE2J1 and UBE2J2. Beyond canonical ERAD, RNF185 has
  documented ligase-dependent regulatory roles that use distinct ubiquitin chain
  topologies. At the mitochondrial outer membrane it builds K63-linked chains on
  the Bcl-2 family protein BNIP1 to promote selective mitochondrial autophagy via
  the autophagy receptor p62, and it builds non-degradative K27-linked chains on
  the DNA sensor cGAS (CGAS) at Lys-173/Lys-384 to enhance its enzymatic activity
  and the cGAS-STING innate antiviral response. RNF185 is ubiquitously expressed;
  its core function is as an ER-membrane ERAD ubiquitin ligase.
alternative_products:
- name: '1'
  id: Q96GF1-1
- name: '2'
  id: Q96GF1-2
  sequence_note: VSP_020004
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 RNF185, conserved across the RNF5/RNF185 family.
    action: ACCEPT
    reason: Core molecular function; supported by multiple IDA/EXP studies (EC 2.3.2.27; RING C39A abolishes activity).
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity
- 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 RNF185.
    action: ACCEPT
    reason: Core biological process; directly supported (CFTR ERAD) and conserved in the family.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway
- term:
    id: GO:0044390
    label: ubiquitin-like protein conjugating enzyme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RNF185 binds ubiquitin-conjugating (E2) enzymes, preferentially the ERAD E2s UBE2J1 and UBE2J2. Informative but ancillary to the ligase activity.
    action: KEEP_AS_NON_CORE
    reason: Accurately reflects E2 binding required for catalysis, but is a mechanistic subsidiary of the core ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA electronic assignment 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 core RING E3 ligase activity.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA electronic assignment of generic cytoplasmic localization; RNF185 has a cytoplasmic N-terminus but is a membrane protein.
    action: KEEP_AS_NON_CORE
    reason: Generic and imprecise; the core localization is the ER membrane. The cytoplasmic topological domain does not make the protein a soluble cytoplasmic protein.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Cytoplasmic
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of mitochondrial outer membrane localization, reflecting the BNIP1/mitochondrial-autophagy study. A real but secondary localization.
    action: KEEP_AS_NON_CORE
    reason: Supported by PMID:21931693 but represents a secondary, autophagy-related localization distinct from the core ER-membrane ERAD function.
    supported_by:
    - reference_id: PMID:21931693
      supporting_text: The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane
- 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 RNF185's ER-membrane ERAD function.
    action: ACCEPT
    reason: Correct compartment; redundant with the more specific ER membrane annotations and IDA evidence.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: All were partially localised to the ER
- 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; the core compartment for RNF185's ERAD function.
    action: ACCEPT
    reason: Correct core localization; supported experimentally (EXP, PMID:27485036).
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:24019521, ECO:0000269|PubMed:27485036}'
- 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 RNF185'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:27485036
      supporting_text: unfolded proteins that accumulate in the ER are transported to the cytosol for ubiquitin-proteasome-mediated degradation
- 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/IGI and IBA evidence.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway
- 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 RNF185 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:27485036
      supporting_text: All were partially localised to the ER
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based assignment of metal (zinc) ion binding by the RING domain, a structural requirement for the ligase fold.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural feature of the RING domain but subsidiary to the informative ubiquitin ligase activity; not a standalone core function.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: RING-type
- 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 IDA/EXP evidence.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-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. RNF185 is a ubiquitin ligase and does not trim mannose; this is pathway-adjacency over-annotation.
    action: REMOVE
    reason: RNF185 has no glycosidase/mannosidase activity; mannose trimming is performed by EDEM/ER mannosidases. This electronic inference is biologically incorrect.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that regulates selective
- 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 RNF185 binding to UBE2D/UBE2E enzymes. 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; P51668: UBE2D1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome map capturing RNF185 partners including RNF5. 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; Q99942: RNF5'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome-community study capturing RNF185 binding to TMBIM6/BI-1. 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; P55061: TMBIM6'
- 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; 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 RNF185 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; P55061: TMBIM6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing RNF185 partners including RNF5. 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/RNF185/RNF185-uniprot.txt
      supporting_text: 'Q96GF1; Q99942: RNF5'
- 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). RNF185 is a ubiquitin ligase, not a transporter; this reflects CFTR/ABC pathway-context bleed-through.
    action: REMOVE
    reason: RNF185 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.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway
- 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 ubiquitination RNF185 performs.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific ERAD pathway and K63/K27 ubiquitination annotations better capture the role.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-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 RNF185 (with RNF5) 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/RNF185/RNF185-uniprot.txt
      supporting_text: The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:21931693
  qualifier: located_in
  review:
    summary: Experimental localization to the mitochondrial outer membrane, where RNF185 ubiquitinates BNIP1 during mitochondrial autophagy. A real but secondary localization.
    action: KEEP_AS_NON_CORE
    reason: Directly supported (PMID:21931693) but a secondary compartment for the autophagy role, not the core ER ERAD function.
    supported_by:
    - reference_id: PMID:21931693
      supporting_text: The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:27485036
  qualifier: located_in
  review:
    summary: Experimental evidence that RNF185 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:27485036
      supporting_text: All were partially localised to the ER
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:21931693
  qualifier: enables
  review:
    summary: Experimental demonstration of RNF185 ubiquitin ligase activity (K63-linked polyubiquitination of BNIP1). Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:21931693
      supporting_text: human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:24019521
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that RNF185 drives ubiquitin-dependent degradation of CFTR. Consistent with the core ERAD/proteasomal degradation role.
    action: ACCEPT
    reason: Supported by RNF185 depletion stabilizing CFTR; consistent with the core ERAD function.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: its silencing stabilizes CFTR proteins
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: Direct evidence of RNF185 RING-dependent ubiquitin ligase activity controlling CFTR stability. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental (IDA) support.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: RNF185 controls the stability of CFTR and of the CFTRΔF508 mutant in a RING- and proteasome-dependent manner
- term:
    id: GO:0045089
    label: positive regulation of innate immune response
  evidence_type: IDA
  original_reference_id: PMID:28273161
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF185 positively regulates the cGAS-mediated innate immune response. A real but secondary, immunity-specific role.
    action: KEEP_AS_NON_CORE
    reason: Well supported (PMID:28273161) but a secondary moonlighting role distinct from the core ER ERAD function.
    supported_by:
    - reference_id: PMID:28273161
      supporting_text: RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity
- 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. RNF185 does not perform mannose trimming; this is pathway-adjacency over-annotation.
    action: REMOVE
    reason: RNF185 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/RNF185/RNF185-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that regulates selective
- term:
    id: GO:0044314
    label: protein K27-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:28273161
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF185 builds non-degradative K27-linked polyubiquitin chains on cGAS, enhancing its activity. A secondary, immunity-related activity.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated K27-linked ubiquitination, but in the context of the secondary cGAS-STING immune role rather than the core ERAD function. K27-linked chain building by RNF185 is corroborated on additional substrates (EBOV GP1,2, PMID:36224200; TUFM, PMID:38084826).
    supported_by:
    - reference_id: PMID:28273161
      supporting_text: RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS
    - reference_id: PMID:36224200
    - reference_id: PMID:38084826
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: IDA
  original_reference_id: PMID:28273161
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF185 contributes to antiviral defense via the cGAS-STING pathway. A real but secondary, immunity-specific role.
    action: KEEP_AS_NON_CORE
    reason: Well supported but a secondary moonlighting role distinct from the core ER ERAD function.
    supported_by:
    - reference_id: PMID:28273161
      supporting_text: the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection
- term:
    id: GO:0060340
    label: positive regulation of type I interferon-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:28273161
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF185 positively regulates type I interferon signaling via cGAS. A real but secondary, immunity-specific role.
    action: KEEP_AS_NON_CORE
    reason: Well supported but a secondary moonlighting role distinct from the core ER ERAD function.
    supported_by:
    - reference_id: PMID:28273161
      supporting_text: Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:28273161
  qualifier: enables
  review:
    summary: Direct evidence of RNF185 ubiquitin ligase activity (K27-linked ubiquitination of cGAS; RING-dependent). Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; C39A/C79A abolishes activity.
    supported_by:
    - reference_id: PMID:28273161
      supporting_text: RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IPI
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: RNF185 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:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:27485036
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization, consistent with RNF185'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: PMID:27485036
      supporting_text: All were partially localised to the ER
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:27485036
  qualifier: enables
  review:
    summary: Direct evidence that RNF185 binds ubiquitin, consistent with its in vitro autoubiquitination/ligase activity.
    action: ACCEPT
    reason: Supported by the in vitro autoubiquitination assays; reflects ubiquitin handling integral to ligase function.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: in vitro autoubiquitination activity
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:27485036
  qualifier: involved_in
  review:
    summary: RNF185 is autoubiquitinated in vitro, a common property of RING E3 ligases reflecting their catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: Supported by in vitro autoubiquitination assays but a secondary property of the ligase, not its core substrate-directed function.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: in vitro autoubiquitination activity
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:27485036
  qualifier: enables
  review:
    summary: Direct evidence of RNF185 E3 activity, with E3-activity-dependent resistance to ER stress. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; RING C39S decreases activity.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner
- term:
    id: GO:1904294
    label: positive regulation of ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:27485036
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that RNF185 positively regulates ERAD, protecting cells from ER stress in an E3-activity-dependent manner. Core biological process.
    action: ACCEPT
    reason: Core biological process; RNF185 is an ER-stress-induced ERAD E3 that confers ER stress resistance.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21931693
  qualifier: enables
  review:
    summary: Interaction with BNIP1, a functionally important RNF185 substrate at the mitochondrial outer membrane. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real RNF185-BNIP1 interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:21931693
      supporting_text: We further identified the Bcl-2 family protein BNIP1 as one of the substrates for RNF185
- 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 RNF185 ER membrane localization within CFTR ERAD reactions. Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 ER membrane localization (CFTR binds ERAD machinery). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: All were partially localised to the 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 RNF185 ER membrane localization (CFTR F508del translocation). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: PMID:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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 RNF185 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:27485036
      supporting_text: All were partially localised to the 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:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24019521
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization in the CFTR ERAD study. Core compartment.
    action: ACCEPT
    reason: IDA-supported ER localization agrees with the documented ER-membrane ERAD function.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: RNF185 is a RING domain-containing polypeptide homologous to RNF5
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:24019521
  qualifier: located_in
  review:
    summary: Author-stated ER membrane localization in the CFTR ERAD study. Core compartment.
    action: ACCEPT
    reason: Consistent with experimentally supported ER-membrane localization.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: RNF185 is a RING domain-containing polypeptide homologous to RNF5
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IGI
  original_reference_id: PMID:24019521
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence (with RNF5) that RNF185 drives ERAD of CFTR; co-depletion blocks CFTR-deltaF508 degradation. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support from the RNF5/RNF185 co-depletion experiments.
    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:0044390
    label: ubiquitin-like protein conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: RNF185 binds the ERAD E2 enzymes UBE2J1/UBE2J2, demonstrated in the CFTR ERAD study. Informative but ancillary to ligase activity.
    action: KEEP_AS_NON_CORE
    reason: Reflects E2 (UBE2J1/UBE2J2) binding required for catalysis, but is a mechanistic subsidiary of the core ligase activity.
    supported_by:
    - reference_id: file:human/RNF185/RNF185-uniprot.txt
      supporting_text: Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24019521
  qualifier: involved_in
  review:
    summary: RNF185 autoubiquitinates, a common RING E3 property reflecting its catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: Supported but a secondary property of the ligase, not its core substrate-directed function.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: RNF185 controls the stability of CFTR and of the CFTRΔF508 mutant in a RING- and proteasome-dependent manner
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: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: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 RNF185 binding to multiple UBE2D/UBE2E enzymes relevant to its catalytic cycle.
- id: PMID:21931693
  title: RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates autophagy through interaction with BNIP1.
  findings:
  - statement: RNF185 is a mitochondrial outer membrane E3 ligase that builds K63-linked polyubiquitin chains on BNIP1 to promote selective mitochondrial autophagy via recruitment of the autophagy receptor p62.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original RNF185 characterization; establishes ligase activity and the non-core mitochondrial-autophagy/BNIP1 role and mitochondrial OM localization.
- 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 is an ER-membrane RING E3 that controls cotranslational ubiquitination and proteasomal degradation of CFTR/CFTR-deltaF508 in a RING- and proteasome-dependent manner; RNF185 and RNF5 form a partly redundant E3 module central to CFTR degradation, preferentially using E2 enzymes UBE2J1/UBE2J2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the core ER-membrane ERAD/CFTR role and RNF5/RNF185 redundancy; source of IMP/IGI/IDA 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 annotations.
- id: PMID:27485036
  title: Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation.
  findings:
  - statement: RNF185 is an ER-stress/UPR-induced ER-localized RING E3 with in vitro autoubiquitination activity that confers ER stress resistance in an E3-activity-dependent manner; the RING domain (Cys-39) is responsible for ligase activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes ER localization, ER-stress induction, E3-activity-dependent ER stress resistance (positive regulation of ERAD).
- id: PMID:28273161
  title: The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response.
  findings:
  - statement: ER-resident RNF185 interacts with cGAS during HSV-1 infection and catalyzes non-degradative K27-linked polyubiquitination of cGAS, enhancing its enzymatic activity and the cGAS-STING type I interferon antiviral response; RING residues Cys-39/Cys-79 are required.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the non-core cGAS-STING immunity role and K27-linked ubiquitination; source of immune-process annotations.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome-community study; source of a bare protein binding annotation (TMBIM6).
- 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 annotations.
- 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 (including RNF5).
- 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:36224200
  title: RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy.
  findings:
  - statement: The ER ubiquitin ligase RNF185 polyubiquitinates misfolded Ebolavirus glycoprotein GP on Lys-673 via K27-linked chains, recruiting SQSTM1/p62 to divert GP to ATG3/ATG5-dependent reticulophagy/ERLAD (lysosomal) rather than proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:36224200 = Nat Commun 2022, DOI 10.1038/s41467-022-33805-9). Extends the RNF185 non-degradative K27-linkage repertoire to a viral ERAD/reticulophagy substrate; full text not in cache, so no supporting_text added.
- id: PMID:38084826
  title: Senecavirus A induces mitophagy to promote self-replication through direct interaction of 2C protein with K27-linked ubiquitinated TUFM catalyzed by RNF185.
  findings:
  - statement: RNF185 catalyzes K27-linked polyubiquitination of the mitochondrial translation elongation factor TUFM (via RNF185 transmembrane domain 1), enabling SQSTM1/p62 recognition and mitophagy that is exploited by Senecavirus A to promote replication.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38084826 = Autophagy 2024, DOI 10.1080/15548627.2023.2293442). Adds a new K27-linked RNF185 substrate (TUFM) and links RNF185 to mitophagy in a viral context; full text not in cache, so no supporting_text added.
- id: PMID:39353943
  title: Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression.
  findings:
  - statement: RNF185 forms an ERAD complex with Membralin (MBRL/TMEM259) that recognizes unassembled Tapasin (a peptide-loading-complex component) and targets it for ubiquitin-dependent degradation; loss of RNF185/Membralin raises Tapasin steady-state levels and increases surface MHC-I, defining an ERAD-based control of antigen presentation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:39353943 = Nat Commun 2024, DOI 10.1038/s41467-024-52772-x). Major new finding identifying the RNF185/Membralin ERAD complex and a new physiological substrate (Tapasin) that links RNF185 to MHC-I antigen presentation; 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 mediates cotranslational ubiquitination of misfolded membrane-protein clients (notably CFTR and CFTR-deltaF508) for proteasomal degradation via the ERAD pathway, acting partly redundantly with RNF5 and preferentially using the E2 enzymes UBE2J1/UBE2J2.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:24019521
    supporting_text: RNF185 controls the stability of CFTR and of the CFTRΔF508 mutant in a RING- and proteasome-dependent manner
  - 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-stress/UPR-induced ER-membrane ubiquitin ligase that positively regulates ERAD and confers resistance to ER stress-induced apoptosis in an E3-activity-dependent manner.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:27485036
    supporting_text: RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner
  directly_involved_in:
  - id: GO:1904294
    label: positive regulation of ERAD pathway
proposed_new_terms: []
suggested_questions:
- question: How is RNF185 partitioned between the ER membrane (ERAD/CFTR) and the mitochondrial outer membrane (BNIP1/mitophagy), and what governs this dual localization and substrate choice?
- question: To what extent are the RNF5 and RNF185 ERAD substrate repertoires overlapping versus distinct, and is their redundancy substrate-specific?
suggested_experiments:
- description: Reconstitute CFTR-deltaF508 ubiquitination in vitro with purified RNF185, RNF5, UBE2J1/UBE2J2 and Derlin cofactors to compare paralog activity and map chain linkages, and perform RNF5/RNF185 single and double knockouts with quantitative ubiquitinome profiling to define overlapping vs distinct ERAD substrates.
- description: Use proximity labeling (BioID/TurboID) of ER-anchored vs mitochondria-anchored RNF185 to map compartment-specific interactomes and test which substrates (CFTR, BNIP1, cGAS) depend on each localization.