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.
| 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 RNF185, conserved across the RNF5/RNF185 family. Reason: Core molecular function; supported by multiple IDA/EXP studies (EC 2.3.2.27; RING C39A abolishes activity). Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity |
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in ER-associated degradation, the core biological process of RNF185. Reason: Core biological process; directly supported (CFTR ERAD) and conserved in the family. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway |
| GO:0044390 ubiquitin-like protein conjugating enzyme binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: RNF185 binds ubiquitin-conjugating (E2) enzymes, preferentially the ERAD E2s UBE2J1 and UBE2J2. Informative but ancillary to the ligase activity. Reason: Accurately reflects E2 binding required for catalysis, but is a mechanistic subsidiary of the core ubiquitin ligase activity. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2 |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic assignment 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 core RING E3 ligase activity. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt EC=2.3.2.27 |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic assignment of generic cytoplasmic localization; RNF185 has a cytoplasmic N-terminus but is a membrane protein. Reason: Generic and imprecise; the core localization is the ER membrane. The cytoplasmic topological domain does not make the protein a soluble cytoplasmic protein. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Cytoplasmic |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of mitochondrial outer membrane localization, reflecting the BNIP1/mitochondrial-autophagy study. A real but secondary localization. Reason: Supported by PMID:21931693 but represents a secondary, autophagy-related localization distinct from the core ER-membrane ERAD function. Supporting Evidence: PMID:21931693 The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of ER localization, consistent with RNF185's ER-membrane ERAD function. Reason: Correct compartment; redundant with the more specific ER membrane annotations and IDA evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; the core compartment for RNF185's ERAD function. Reason: Correct core localization; supported experimentally (EXP, PMID:27485036). Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:24019521, ECO:0000269|PubMed:27485036} |
| 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 RNF185's ERAD role. Reason: Correct but generic; the specific GO:0036503 (ERAD pathway) better captures the core biological role. Supporting Evidence: PMID:27485036 unfolded proteins that accumulate in the ER are transported to the cytosol for ubiquitin-proteasome-mediated degradation |
| 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/IGI and IBA evidence. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway |
| GO:0044322 endoplasmic reticulum quality control compartment | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology logical inference placing RNF185 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:27485036 All were partially localised to the ER |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based assignment of metal (zinc) ion binding by the RING domain, a structural requirement for the ligase fold. Reason: Accurate structural feature of the RING domain but subsidiary to the informative ubiquitin ligase activity; not a standalone core function. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt RING-type |
| 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 IDA/EXP evidence. Supporting Evidence: file:human/RNF185/RNF185-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. RNF185 is a ubiquitin ligase and does not trim mannose; this is pathway-adjacency over-annotation. Reason: RNF185 has no glycosidase/mannosidase activity; mannose trimming is performed by EDEM/ER mannosidases. This electronic inference is biologically incorrect. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt E3 ubiquitin-protein ligase that regulates selective |
| 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 RNF185 binding to UBE2D/UBE2E enzymes. 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/RNF185/RNF185-uniprot.txt Q96GF1; P51668: UBE2D1 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome map capturing RNF185 partners including RNF5. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Q96GF1; Q99942: RNF5 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interactome-community study capturing RNF185 binding to TMBIM6/BI-1. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Q96GF1; P55061: TMBIM6 |
| 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/RNF185/RNF185-uniprot.txt Q96GF1; 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 RNF185 membrane-protein partners. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Q96GF1; P55061: TMBIM6 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome capturing RNF185 partners including RNF5. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Q96GF1; Q99942: RNF5 |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | REMOVE | Summary: Reactome pathway-level annotation (ABC-family transport). RNF185 is a ubiquitin ligase, not a transporter; this reflects CFTR/ABC pathway-context bleed-through. 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. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway |
| 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 ubiquitination RNF185 performs. Reason: Correct but generic; the specific ERAD pathway and K63/K27 ubiquitination annotations better capture the role. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0061630 ubiquitin protein ligase activity | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of RNF185 (with RNF5) 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/RNF185/RNF185-uniprot.txt The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity |
| GO:0005741 mitochondrial outer membrane | EXP PMID:21931693 RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates... | KEEP AS NON CORE | Summary: Experimental localization to the mitochondrial outer membrane, where RNF185 ubiquitinates BNIP1 during mitochondrial autophagy. A real but secondary localization. Reason: Directly supported (PMID:21931693) but a secondary compartment for the autophagy role, not the core ER ERAD function. Supporting Evidence: PMID:21931693 The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:27485036 Genome-wide identification and gene expression profiling of ... | ACCEPT | Summary: Experimental evidence that RNF185 localizes to the ER membrane; the core compartment for its ERAD ligase activity. Reason: Core localization with direct experimental support. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:21931693 RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates... | ACCEPT | Summary: Experimental demonstration of RNF185 ubiquitin ligase activity (K63-linked polyubiquitination of BNIP1). Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:21931693 human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells |
| GO:0006511 ubiquitin-dependent protein catabolic process | IMP PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Mutant-phenotype evidence that RNF185 drives ubiquitin-dependent degradation of CFTR. Consistent with the core ERAD/proteasomal degradation role. Reason: Supported by RNF185 depletion stabilizing CFTR; consistent with the core ERAD function. Supporting Evidence: PMID:24019521 its silencing stabilizes CFTR proteins |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Direct evidence of RNF185 RING-dependent ubiquitin ligase activity controlling CFTR stability. Core molecular function. Reason: Core molecular function with direct experimental (IDA) support. Supporting Evidence: PMID:24019521 RNF185 controls the stability of CFTR and of the CFTRΞF508 mutant in a RING- and proteasome-dependent manner |
| GO:0045089 positive regulation of innate immune response | IDA PMID:28273161 The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated... | KEEP AS NON CORE | Summary: Direct evidence that RNF185 positively regulates the cGAS-mediated innate immune response. A real but secondary, immunity-specific role. Reason: Well supported (PMID:28273161) but a secondary moonlighting role distinct from the core ER ERAD function. Supporting Evidence: PMID:28273161 RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity |
| GO:1904380 endoplasmic reticulum mannose trimming | TAS Reactome:R-HSA-901032 | REMOVE | Summary: Reactome ERQC pathway annotation. RNF185 does not perform mannose trimming; this is pathway-adjacency over-annotation. 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. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt E3 ubiquitin-protein ligase that regulates selective |
| GO:0044314 protein K27-linked ubiquitination | IDA PMID:28273161 The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated... | KEEP AS NON CORE | Summary: Direct evidence that RNF185 builds non-degradative K27-linked polyubiquitin chains on cGAS, enhancing its activity. A secondary, immunity-related activity. 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). Supporting Evidence: PMID:28273161 RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS |
| GO:0051607 defense response to virus | IDA PMID:28273161 The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated... | KEEP AS NON CORE | Summary: Direct evidence that RNF185 contributes to antiviral defense via the cGAS-STING pathway. A real but secondary, immunity-specific role. Reason: Well supported but a secondary moonlighting role distinct from the core ER ERAD function. Supporting Evidence: PMID:28273161 the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection |
| GO:0060340 positive regulation of type I interferon-mediated signaling pathway | IDA PMID:28273161 The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated... | KEEP AS NON CORE | Summary: Direct evidence that RNF185 positively regulates type I interferon signaling via cGAS. A real but secondary, immunity-specific role. Reason: Well supported but a secondary moonlighting role distinct from the core ER ERAD function. Supporting Evidence: PMID:28273161 Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:28273161 The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated... | ACCEPT | Summary: Direct evidence of RNF185 ubiquitin ligase activity (K27-linked ubiquitination of cGAS; RING-dependent). Core molecular function. Reason: Core molecular function with direct experimental support; C39A/C79A abolishes activity. Supporting Evidence: PMID:28273161 RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS |
| GO:0044877 protein-containing complex binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | KEEP AS NON CORE | Summary: RNF185 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:0005783 endoplasmic reticulum | IDA PMID:27485036 Genome-wide identification and gene expression profiling of ... | ACCEPT | Summary: Direct evidence for ER localization, consistent with RNF185's ER-membrane ERAD function. Reason: IDA-supported ER localization agrees with the documented ER-membrane site of action. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0043130 ubiquitin binding | IDA PMID:27485036 Genome-wide identification and gene expression profiling of ... | ACCEPT | Summary: Direct evidence that RNF185 binds ubiquitin, consistent with its in vitro autoubiquitination/ligase activity. Reason: Supported by the in vitro autoubiquitination assays; reflects ubiquitin handling integral to ligase function. Supporting Evidence: PMID:27485036 in vitro autoubiquitination activity |
| GO:0051865 protein autoubiquitination | IDA PMID:27485036 Genome-wide identification and gene expression profiling of ... | KEEP AS NON CORE | Summary: RNF185 is autoubiquitinated in vitro, a common property of RING E3 ligases reflecting their catalytic activity. Reason: Supported by in vitro autoubiquitination assays but a secondary property of the ligase, not its core substrate-directed function. Supporting Evidence: PMID:27485036 in vitro autoubiquitination activity |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:27485036 Genome-wide identification and gene expression profiling of ... | ACCEPT | Summary: Direct evidence of RNF185 E3 activity, with E3-activity-dependent resistance to ER stress. Core molecular function. Reason: Core molecular function with direct experimental support; RING C39S decreases activity. Supporting Evidence: PMID:27485036 RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner |
| GO:1904294 positive regulation of ERAD pathway | IMP PMID:27485036 Genome-wide identification and gene expression profiling of ... | ACCEPT | Summary: Mutant-phenotype evidence that RNF185 positively regulates ERAD, protecting cells from ER stress in an E3-activity-dependent manner. Core biological process. Reason: Core biological process; RNF185 is an ER-stress-induced ERAD E3 that confers ER stress resistance. Supporting Evidence: PMID:27485036 RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner |
| GO:0005515 protein binding | IPI PMID:21931693 RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates... | KEEP AS NON CORE | Summary: Interaction with BNIP1, a functionally important RNF185 substrate at the mitochondrial outer membrane. Bare protein binding is uninformative. Reason: Records the real RNF185-BNIP1 interaction but bare protein binding is uninformative. Supporting Evidence: PMID:21931693 We further identified the Bcl-2 family protein BNIP1 as one of the substrates for RNF185 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization within CFTR ERAD reactions. Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (RNF5/RNF185 ubiquitinate misfolded CFTR). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (CFTR binds ERAD machinery). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (CFTR F508del translocation). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (RNF5/RNF185 ubiquitinate CFTR F508del). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (CFTR F508del binds ERAD machinery). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8867288 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization in an ERAD ubiquitination reaction. Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (CD274/PD-L1 ERAD transport). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (ubiquitination of CD274 by ERAD complex). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: Reactome curation of RNF185 ER membrane localization (p-CD274 binds ERAD complex). Core compartment. Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: PMID:27485036 All were partially localised to the 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:0005783 endoplasmic reticulum | IDA PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Direct evidence for ER localization in the CFTR ERAD study. Core compartment. Reason: IDA-supported ER localization agrees with the documented ER-membrane ERAD function. Supporting Evidence: PMID:24019521 RNF185 is a RING domain-containing polypeptide homologous to RNF5 |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Author-stated ER membrane localization in the CFTR ERAD study. Core compartment. Reason: Consistent with experimentally supported ER-membrane localization. Supporting Evidence: PMID:24019521 RNF185 is a RING domain-containing polypeptide homologous to RNF5 |
| GO:0036503 ERAD pathway | IGI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Genetic-interaction evidence (with RNF5) that RNF185 drives ERAD of CFTR; co-depletion blocks CFTR-deltaF508 degradation. Core biological process. Reason: Core biological process with direct experimental support from the RNF5/RNF185 co-depletion experiments. 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:0044390 ubiquitin-like protein conjugating enzyme binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | KEEP AS NON CORE | Summary: RNF185 binds the ERAD E2 enzymes UBE2J1/UBE2J2, demonstrated in the CFTR ERAD study. Informative but ancillary to ligase activity. Reason: Reflects E2 (UBE2J1/UBE2J2) binding required for catalysis, but is a mechanistic subsidiary of the core ligase activity. Supporting Evidence: file:human/RNF185/RNF185-uniprot.txt Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2 |
| GO:0051865 protein autoubiquitination | IDA PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | KEEP AS NON CORE | Summary: RNF185 autoubiquitinates, a common RING E3 property reflecting its catalytic activity. Reason: Supported but a secondary property of the ligase, not its core substrate-directed function. Supporting Evidence: PMID:24019521 RNF185 controls the stability of CFTR and of the CFTRΞF508 mutant in a RING- and proteasome-dependent manner |
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Download this section (compressed HTML)Q: 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?
Q: To what extent are the RNF5 and RNF185 ERAD substrate repertoires overlapping versus distinct, and is their redundancy substrate-specific?
Experiment: 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.
Experiment: 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.
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