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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of RING-type ubiquitin ligase activity, the core molecular function of RNF5, conserved across the RNF5/RNF185 family. Reason: Core molecular function; supported experimentally (EC 2.3.2.27; C42S abolishes activity) and across the family. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins |
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in ER-associated degradation, the core biological process of RNF5 as an ER-anchored ERAD ligase. Reason: Core biological process; directly supported by IMP evidence (CFTR/CFTR-deltaF508 degradation) and conserved in the family. Supporting Evidence: PMID:24019521 Cystic fibrosis transmembrane conductance regulator (CFTR) is one ERAD substrate targeted to co-translational degradation by the E3 ligase RNF5/RMA1 |
| GO:0044390 ubiquitin-like protein conjugating enzyme binding | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: Accurately reflects E2 binding (UBE2D1/UBE2D2, UBE2N) required for catalysis, but is a mechanistic subsidiary of the core ubiquitin ligase activity. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt May function together with E2 ubiquitin-conjugating enzymes UBE2D1/UBCH5A and UBE2D2/UBC4 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of ER localization, consistent with RNF5's ER-membrane site of ERAD function. Reason: Correct compartment; redundant with the more specific ER membrane annotations and IDA (HPA) evidence. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439} |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; this is the core compartment for RNF5's ERAD ligase function. Reason: Correct core localization; RNF5 is a tail-anchored ER membrane protein, supported experimentally (EXP, PMID:19285439). Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439} |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Reported in the early cloning paper but the functionally dominant compartment for RNF5 is the ER membrane; plasma membrane pool is peripheral. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Cell membrane {ECO:0000269|PubMed:9533025} |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of ubiquitin-dependent protein catabolism, a parent process consistent with RNF5's ERAD role. Reason: Correct but generic; the specific GO:0036503 (ERAD pathway) better captures the core biological role. Supporting Evidence: PMID:24019521 degraded by the ubiquitin-proteasome pathway through a process called ER-associated degradation (ERAD) |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Supported by PMID:19285439 (MITA ubiquitination at mitochondria) but represents a secondary, context-specific role distinct from the core ER-membrane ERAD function. Supporting Evidence: PMID:19285439 virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria |
| GO:0036503 ERAD pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning electronic assignment of the ERAD pathway, redundant with the experimentally supported core process. Reason: Correct core biological process; redundant with IMP and IBA evidence. Supporting Evidence: PMID:24019521 Cystic fibrosis transmembrane conductance regulator (CFTR) is one ERAD substrate targeted to co-translational degradation by the E3 ligase RNF5/RMA1 |
| GO:0044322 endoplasmic reticulum quality control compartment | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology logical inference placing RNF5 in the ER quality control compartment, a plausible localization derived from its ERAD role. Reason: Plausible localization inferred from the ERAD/ERQC link, but not directly demonstrated; the core localization annotation is ER membrane. Supporting Evidence: PMID:24019521 hosts a machinery called ERQC for ER quality control |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic assignment of the core RING E3 ligase activity, consistent with EC 2.3.2.27 and experimental evidence. Reason: Correct core molecular function; redundant with EXP/IBA evidence. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt EC=2.3.2.27 |
| GO:1904380 endoplasmic reticulum mannose trimming | IEA GO_REF:0000117 | REMOVE | 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. 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. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins |
| GO:0005515 protein binding | IPI PMID:12861019 RNF5, a RING finger protein that regulates cell motility by ... | KEEP AS NON CORE | Summary: IntAct interaction with paxillin (PXN), a functionally meaningful RNF5 substrate, but the bare protein binding term is uninformative. Reason: Records a real substrate interaction (PXN) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:12861019 the human homologue of RNF5 associates with the amino-terminal domain of paxillin |
| GO:0005515 protein binding | IPI PMID:14667819 Analysis of a high-throughput yeast two-hybrid system and it... | KEEP AS NON CORE | Summary: High-throughput yeast two-hybrid interactions (e.g. ABHD16A, UBE2 enzymes). Bare protein binding is uninformative. Reason: Records real IntAct interactions but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; O95870: ABHD16A |
| GO:0005515 protein binding | IPI PMID:16901789 Sequential quality-control checkpoints triage misfolded cyst... | KEEP AS NON CORE | Summary: Interaction with CFTR captured in the sequential-triage ERAD study; CFTR is a key RNF5 ERAD substrate. Bare protein binding is uninformative. Reason: Records the functionally important RNF5-CFTR interaction, but bare protein binding is uninformative; the substrate relationship is captured by the ERAD process annotations. Supporting Evidence: PMID:16901789 an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1, the E2 Ubc6e, and Derlin-1 |
| GO:0005515 protein binding | IPI PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protei... | KEEP AS NON CORE | Summary: E2 ubiquitin-conjugating enzyme interaction network capturing RNF5 binding to multiple UBE2D/UBE2E/UBE2W E2s. Bare protein binding is uninformative. Reason: Real E2 interactions relevant to catalysis but bare protein binding is uninformative; E2 binding is captured by GO:0044390. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; P51668: UBE2D1 |
| GO:0005515 protein binding | IPI PMID:20152160 Crystal structure of UbcH5b~ubiquitin intermediate: insight ... | KEEP AS NON CORE | Summary: Interaction with the E2 UBE2D2/UbcH5b from a structural study of the E2~Ub conjugate. Bare protein binding is uninformative. Reason: Real E2 interaction but bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; P62837: UBE2D2 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Large-scale interactome map capturing numerous RNF5 partners (including SLC transporters, RNF185, SEC22A). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q96GF1: RNF185 |
| GO:0005515 protein binding | IPI PMID:25759021 Regulation of glutamine carrier proteins by RNF5 determines ... | KEEP AS NON CORE | Summary: Interactions with glutamine carrier proteins (SLC1A5, SLC38A2) relevant to RNF5's role in breast cancer ER-stress response. Bare protein binding is uninformative. Reason: Records real substrate/carrier interactions but bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q15758: SLC1A5 |
| GO:0005515 protein binding | IPI PMID:26618866 βF508 CFTR interactome remodelling promotes rescue of cystic... | KEEP AS NON CORE | Summary: Interaction with CFTR from a deltaF508 CFTR interactome-remodeling study. Bare protein binding is uninformative. Reason: Real CFTR interaction relevant to ERAD but bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; P13569: CFTR |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Interaction captured in a study of variant-driven interactome disruption. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q969T4: UBE2E3 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map capturing many RNF5 membrane-protein partners. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q9Y5U4: INSIG2 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Interactions (e.g. OPTN, UBE2K) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q96CV9: OPTN |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome capturing RNF5 partners including RNF185 and RHBDD1. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q96GF1: RNF185 |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | KEEP AS NON CORE | Summary: Proximity-labeling interaction with CFTR identifying enrichment in SLC transporters. Bare protein binding is uninformative. Reason: Real CFTR/SLC interactions but bare protein binding is uninformative. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; P13569: CFTR |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: RNF5 self-interaction captured in a proteome-scale interactome. Reflects homo-association seen in screens. Reason: Documents RNF5 self-association (IntAct EBI-348482 with itself) but is peripheral to the core ligase function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q99942: RNF5 |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: RNF5 self-interaction captured in the binary interactome reference map. Reason: Documents RNF5 self-association but is peripheral to the core ligase function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Q99942; Q99942: RNF5 |
| GO:0016020 membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of generic membrane localization, a parent of the specific ER membrane localization. Reason: Correct but generic; subsumed by the more specific ER membrane localization. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Multi-pass membrane protein |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | REMOVE | 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. 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. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific ERAD-associated ubiquitination RNF5 performs. Reason: Correct but generic; the specific ERAD pathway and K48/K63 ubiquitination annotations better capture the role. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0061630 ubiquitin protein ligase activity | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of RNF5 (with RNF185) ubiquitinating misfolded CFTR; captures the core ligase activity. Reason: Correct core molecular function in the CFTR ERAD reaction. Supporting Evidence: PMID:24019521 identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation |
| GO:0061630 ubiquitin protein ligase activity | TAS Reactome:R-HSA-8867288 | ACCEPT | Summary: Reactome curation of the ERAD E3 ligase ubiquitinating an unfolded glycoprotein substrate; captures the core ligase activity. Reason: Correct core molecular function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with RNF5's ER-membrane ERAD function. Reason: IDA-supported ER localization agrees with the documented ER-membrane site of action. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:19285439} |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:19285439 The ubiquitin ligase RNF5 regulates antiviral responses by m... | ACCEPT | Summary: Experimental evidence that RNF5 localizes to the ER membrane; the core compartment for its ERAD ligase activity. Reason: Core localization with direct experimental support. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005886 plasma membrane | EXP PMID:9533025 Cloning, expression and mapping of a novel RING-finger gene ... | KEEP AS NON CORE | Summary: Experimental localization to the plasma membrane reported in the original cloning study. A real but secondary localization. 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. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Predominantly located in the plasma membrane, with some localization occurring within cytoplasmic organelles |
| GO:0031966 mitochondrial membrane | EXP PMID:19285439 The ubiquitin ligase RNF5 regulates antiviral responses by m... | KEEP AS NON CORE | Summary: Experimental localization to the mitochondrial membrane, where RNF5 ubiquitinates STING1/MITA during antiviral responses. A real but secondary, immunity-related localization. Reason: Directly supported (PMID:19285439) but a secondary compartment for a context-specific immune role, not the core ER ERAD function. Supporting Evidence: PMID:19285439 virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:19269966 Regulation of endoplasmic reticulum-associated degradation b... | ACCEPT | Summary: Experimental demonstration of RNF5 ubiquitin ligase activity (RING-dependent ubiquitination of JAMP). Core molecular function. Reason: Core molecular function with direct experimental support; WT but not RING-mutant RNF5 ubiquitinates substrate. Supporting Evidence: PMID:19269966 Ectopically expressed JAMP was efficiently ubiquitinated in vivo by WT but not the RING mutant form of RNF5 |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:19285439 The ubiquitin ligase RNF5 regulates antiviral responses by m... | ACCEPT | Summary: Experimental demonstration of RNF5 ligase activity ubiquitinating STING1/MITA. Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:19285439 RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:23093945 Regulation of ATG4B stability by RNF5 limits basal levels of... | ACCEPT | Summary: Experimental demonstration of RNF5 ligase activity controlling ATG4B ubiquitination and stability. Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:23093945 the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B |
| GO:0006511 ubiquitin-dependent protein catabolic process | IGI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Genetic-interaction evidence (with RNF185) that RNF5 drives ubiquitin-dependent degradation of CFTR; redundant depletion blocks CFTR-deltaF508 turnover. Reason: Supported by the RNF5/RNF185 co-depletion experiments; consistent with the core ERAD/proteasomal degradation role. Supporting Evidence: PMID:24019521 simultaneous depletion of RNF5 and RNF185 profoundly blocks CFTRΞF508 degradation not only during translation but also after synthesis is complete |
| GO:0036503 ERAD pathway | IMP PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Mutant-phenotype evidence that RNF5 is required for ERAD of CFTR/CFTR-deltaF508. Core biological process. Reason: Core biological process with direct experimental (IMP) support from depletion experiments. Supporting Evidence: PMID:24019521 simultaneous depletion of RNF5 and RNF185 profoundly blocks CFTRΞF508 degradation |
| GO:0061630 ubiquitin protein ligase activity | TAS PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Author statement of RNF5 ubiquitin ligase activity in CFTR ERAD. Core molecular function. Reason: Correct core molecular function. Supporting Evidence: PMID:24019521 targeted to co-translational degradation by the E3 ligase RNF5/RMA1 |
| GO:1904380 endoplasmic reticulum mannose trimming | TAS Reactome:R-HSA-901032 | REMOVE | Summary: Reactome ERQC pathway annotation. RNF5 does not perform mannose trimming; this is pathway-adjacency over-annotation. 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. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins |
| GO:0044877 protein-containing complex binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | KEEP AS NON CORE | Summary: RNF5 binds a protein complex (ERAD machinery) in the CFTR degradation study. More informative than bare protein binding but still ancillary. Reason: Reflects association with the ERAD E3 module/machinery; supportive of, but subsidiary to, the core ligase and ERAD-process annotations. Supporting Evidence: PMID:24019521 identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization within CFTR ERAD reactions. Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (RNF5/RNF185 ubiquitinate misfolded CFTR). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (CFTR binds ERAD machinery). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (CFTR F508del translocation). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (RNF5/RNF185 ubiquitinate CFTR F508del). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (CFTR F508del binds ERAD machinery). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8867288 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization in an ERAD ubiquitination reaction. Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (CD274/PD-L1 ERAD transport). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (ubiquitination of CD274 by ERAD complex). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: Reactome curation of RNF5 ER membrane localization (p-CD274 binds ERAD complex). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:19285439 Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) |
| GO:0005515 protein binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | KEEP AS NON CORE | Summary: Interaction captured in the RNF185/RNF5 CFTR ERAD study. Bare protein binding is uninformative. Reason: Real interaction within the ERAD module but bare protein binding is uninformative. Supporting Evidence: PMID:24019521 identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation |
| GO:0030163 protein catabolic process | IMP PMID:19285439 The ubiquitin ligase RNF5 regulates antiviral responses by m... | KEEP AS NON CORE | 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. Reason: Correct but generic relative to the specific ERAD and K48-ubiquitination annotations; here the catabolic target is the immune adaptor MITA. Supporting Evidence: PMID:19285439 RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:19285439 The ubiquitin ligase RNF5 regulates antiviral responses by m... | ACCEPT | Summary: Direct evidence that RNF5 builds K48-linked polyubiquitin chains (degradative topology) on STING1/MITA. This degradative topology is also used on CFTR. Reason: Directly demonstrated K48-linked ubiquitination, the canonical degradative topology underlying RNF5's ERAD and MITA-degradation roles. Supporting Evidence: PMID:19269966 CFTR ubiquitination occurred at the canonical Lys-48 topology |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19269966 Regulation of endoplasmic reticulum-associated degradation b... | ACCEPT | Summary: Direct evidence of ubiquitin-protein transferase activity, a parent of the specific RING-type ubiquitin ligase activity. Reason: Correct general molecular function; the specific GO:0061630 captures the RING E3 ligase activity. Supporting Evidence: PMID:19269966 Ectopically expressed JAMP was efficiently ubiquitinated in vivo by WT but not the RING mutant form of RNF5 |
| GO:0005515 protein binding | IPI PMID:19269966 Regulation of endoplasmic reticulum-associated degradation b... | KEEP AS NON CORE | Summary: Interaction with JKAMP/JAMP, a functionally important RNF5 substrate/partner at the ER membrane. Bare protein binding is uninformative. Reason: Records the real RNF5-JAMP interaction but bare protein binding is uninformative. Supporting Evidence: PMID:19269966 RNF5 associates with JAMP in the ER membrane |
| GO:0036503 ERAD pathway | IMP PMID:19269966 Regulation of endoplasmic reticulum-associated degradation b... | ACCEPT | Summary: Mutant-phenotype evidence linking RNF5 to ERAD, here via regulation of the ERAD adaptor JAMP. Core biological process. Reason: Core biological process; RNF5 modulates ERAD both by direct substrate ubiquitination and by K63-regulation of JAMP. Supporting Evidence: PMID:19269966 RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins |
| GO:0070534 protein K63-linked ubiquitination | IDA PMID:19269966 Regulation of endoplasmic reticulum-associated degradation b... | ACCEPT | Summary: Direct evidence that RNF5 builds non-degradative K63-linked polyubiquitin chains on JAMP (Ubc13/UBE2N-dependent), a regulatory rather than degradative modification. Reason: Directly demonstrated K63-linked ubiquitination, establishing RNF5's capacity for non-canonical regulatory ubiquitination distinct from K48 degradative chains. Supporting Evidence: PMID:19269966 These findings establish that RNF5 mediates Lys-63-based polyubiquitination of JAMP |
| GO:0008270 zinc ion binding | TAS PMID:9533025 Cloning, expression and mapping of a novel RING-finger gene ... | KEEP AS NON CORE | 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. Reason: Accurate structural feature of the RING domain (residues 27-68) but subsidiary to the informative ubiquitin ligase activity; not a standalone core function. Supporting Evidence: file:human/RNF5/RNF5-uniprot.txt RING-type |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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