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RNF186

E3 ubiquitin-protein ligase RNF186 · UniProt Q9NXI6

Length
227 aa
Mass
24.1 kDa
Annotated
2026-06-10
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF186 is an endoplasmic reticulum-resident RING-finger E3 ubiquitin ligase that controls intestinal homeostasis, innate immune signaling, and metabolic adaptation by ubiquitinating a diverse panel of substrates in a cell-type- and stimulus-dependent manner (PMID:23896122, PMID:27381925, PMID:34623328). In its founding role it ubiquitinates BNip1 via K29/K63-linked chains to drive its mitochondrial translocation and amplify ER-stress apoptosis, while autoregulating its own abundance through self-ubiquitination that is suppressed under ER stress (PMID:23896122). In colonic epithelium RNF186 maintains barrier integrity by polyubiquitinating occludin, and its E3 activity protects against DSS colitis (PMID:27381925); it also ubiquitinates EPHB2, either at K892 to recruit MAP1LC3B and activate cytoprotective autophagy (PMID:33280498) or to scaffold TAB2 tyrosine phosphorylation and TAK1 engagement that propagates TNF signaling and colitis-associated tumorigenesis (PMID:36130827). In macrophages responding to NOD2 and other pattern-recognition receptors, RNF186 ubiquitinates ATF6 at K152 to induce the unfolded protein response, cytokine secretion, ROS/RNS production, and bacterial clearance (PMID:34623328, PMID:34353900). Through ubiquitin-dependent degradation of substrates it also regulates metabolism: targeting Sestrin-2 at K13 to relieve mTORC1 inhibition (PMID:31586034), and degrading cytoplasmic HMGB1 via K48/K63 chains to restrain lipophagy and lipid accumulation in hepatocytes (PMID:38158076). IBD/UC-associated variants A64T and R179X reduce or abolish RNF186 ligase function and alter its localization, linking these activities to inflammatory bowel disease (PMID:27381925, PMID:27503255, PMID:34623328, PMID:34353900).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2013 Medium

    Established RNF186 as a functional ER-localized RING E3 ligase with a defined substrate, answering whether it had catalytic activity and a biological output.

    Evidence Co-localization, reciprocal Co-IP, in vivo ubiquitination with linkage typing, and KD/OE in HeLa cells

    PMID:23896122

    Open questions at the time
    • Mechanism of BNip1 mitochondrial targeting by non-degradative chains not resolved
    • Generality beyond HeLa not tested
    • ER retention determinants not mapped
  2. 2016 High

    Connected RNF186 to intestinal barrier function and IBD by showing its ligase activity controls occludin and that a UC-associated mutation impairs it, plus that a truncating variant mislocalizes the protein.

    Evidence Rnf186 knockout and knock-in mice, DSS colitis, permeability assays; human genetic cohort with R179X localization analysis

    PMID:27381925 PMID:27503255

    Open questions at the time
    • Direct ubiquitination of occludin not biochemically reconstituted
    • Linkage type on occludin unspecified
    • Relationship between barrier and ER-stress phenotypes unresolved
  3. 2018 Medium

    Extended RNF186 to hepatic metabolism, showing gain-of-function induces ER stress that impairs insulin signaling, framing it as a metabolic stress modulator.

    Evidence Adenoviral overexpression in primary mouse hepatocytes with ER-stress/insulin readouts and TUDCA rescue

    PMID:30223017

    Open questions at the time
    • Substrate driving hepatic ER stress not identified here
    • Overexpression-only, no loss-of-function
    • Physiological relevance to whole-animal metabolism untested
  4. 2019 High

    Identified Sestrin-2 as a degradative substrate, linking RNF186 to nutrient sensing and mTORC1 activation through an acceptor-site-defined mechanism.

    Evidence siRNA E3-ligase screen, Co-IP, in vitro ubiquitination, K13 mutagenesis, mTORC1 signaling readouts

    PMID:31586034

    Open questions at the time
    • In vivo metabolic consequence of the axis not established
    • Chain linkage on Sestrin-2 not detailed
    • Cell-type breadth of axis unknown
  5. 2020 High

    Defined a second epithelial substrate, EPHB2, whose K892 ubiquitination recruits LC3B to activate protective autophagy, and showed both genes are required to limit colitis.

    Evidence Co-IP, in vivo ubiquitination with K892R mutagenesis, KO mouse DSS colitis, autophagy flux and LC3B recruitment assays

    PMID:33280498

    Open questions at the time
    • How ubiquitinated EPHB2 recruits LC3B structurally unresolved
    • Chain linkage unspecified
    • Relationship to EPHB2's TNF-signaling role not reconciled here
  6. 2020 Medium

    Showed RNF186 suppresses NF-κB and tumor growth in colorectal cancer, positioning it as tumor-suppressive in this context.

    Evidence CRC cell overexpression, NF-κB phosphorylation assays, AOM/DSS tumor model with KO mice, Ki67 staining

    PMID:32882406

    Open questions at the time
    • Direct substrate mediating NF-κB suppression not identified
    • Apparent contrast with pro-tumor TNF-signaling role unresolved
    • Mechanism linking ligase activity to NF-κB phosphorylation unclear
  7. 2021 High

    Defined RNF186's macrophage innate-immune function by identifying ATF6 (K152) as a substrate required for NOD2/PRR-induced UPR, and showed the broad PRR signaling and bacterial-clearance roles plus loss-of-function of IBD risk variants.

    Evidence Human macrophage transfection/KD, Co-IP with ER stress sensors, in vivo ubiquitination with K152 mutagenesis, KO mice with Salmonella/DSS challenge, ROS/RNS and clearance assays, A64T variant characterization

    PMID:34353900 PMID:34623328

    Open questions at the time
    • Identity of all PRR signaling-complex substrates incompletely defined
    • How a single ligase achieves PRR-specific versus shared ubiquitination unclear
    • Integration of ATF6/UPR with autophagy and ROS outputs unresolved
  8. 2022 High

    Showed RNF186-ubiquitinated EPHB2 scaffolds TAB2 tyrosine phosphorylation and TAK1 binding to drive TNF signaling and colitis-associated tumorigenesis, revealing a pro-inflammatory output of the same substrate used for autophagy.

    Evidence Co-IP, ubiquitination assay, TAB2 phospho-site mapping, KO mouse AOM/DSS tumor model, EPHB2 gain-of-function analysis

    PMID:36130827

    Open questions at the time
    • What dictates EPHB2 routing toward autophagy versus TAB2-TAK1 signaling unknown
    • Kinase phosphorylating TAB2 tyrosines not defined
    • Reconciliation with tumor-suppressive NF-κB role unresolved
  9. 2023 High

    Identified cytoplasmic HMGB1 as a degradative substrate, establishing RNF186 as a restraint on lipophagy and hepatic lipid accumulation in NAFLD.

    Evidence RNF186 KO mice, primary hepatocyte KD/KO, in vivo ubiquitination with linkage-specific antibodies, HMGB1 fractionation, autophagy flux, HMGB1-knockdown epistasis

    PMID:38158076

    Open questions at the time
    • Selectivity for cytoplasmic over nuclear HMGB1 mechanism unclear
    • How K63 chains route HMGB1 to proteasome not resolved
    • Link between HMGB1 degradation and earlier hepatic ER-stress phenotype unexplored
  10. 2025 Medium

    Extended the ATF6/UPR axis to skeletal muscle glucose handling, showing RNF186 deficiency raises GLUT4 expression and membrane translocation via reduced UPR and AKT/TBC1D4 signaling.

    Evidence RNF186 KO mice on HFD, high-glucose myocyte/hepatocyte models, ATF6 ubiquitination and UPR blots, GLUT4 immunofluorescence, AKT/TBC1D4 phospho-assays

    PMID:41316307

    Open questions at the time
    • Direct link between ATF6 ubiquitination and AKT/TBC1D4 pathway not mechanistically connected
    • Single lab, recent
    • Whole-body glucose homeostasis consequences not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single ER ligase selects among its many context-specific substrates and switches between cytoprotective (autophagy, UPR) and pro-inflammatory/pro-apoptotic outputs.
  • No structural model of substrate recognition
  • Stimulus-to-substrate routing rules undefined
  • Apparent tumor-suppressive versus pro-tumor roles not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 5
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2
Partners
ATF6BNIP1EPHB2HMGB1OCLNSESN2TAB2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 RNF186 is an ER-localized RING finger E3 ubiquitin ligase that ubiquitinates BNip1 via K29- and K63-linked polyubiquitin chains in vivo, promoting BNip1 translocation to mitochondria without affecting its protein level, thereby amplifying ER stress-associated apoptotic signaling. RNF186 also undergoes self-ubiquitination and proteasomal degradation, which is inhibited under ER stress conditions, stabilizing RNF186 and enhancing BNip1 ubiquitination. Co-localization, co-immunoprecipitation, in vivo ubiquitination assay, overexpression and knockdown in HeLa cells, Ca2+ flux measurement, half-life assay Cellular signalling Medium 23896122
2016 RNF186 acts as an E3 ligase that mediates polyubiquitination of substrates including occludin in colonic epithelial cells; loss of RNF186 in Rnf186-/- mice leads to increased occludin levels, augmented intestinal permeability to small organic molecules, enhanced ER stress in colonic epithelia, and increased sensitivity to DSS-induced intestinal inflammation. An UC-associated Rnf186 mutation impairs E3 ligase activity in vivo. Rnf186 knockout mouse model, DSS colitis model, intestinal permeability assay, western blot for substrates and ER stress markers, knock-in UC-associated mutation Mucosal immunology High 27381925
2016 The protein-truncating R179X variant of RNF186 exhibits reduced protein expression and altered subcellular localization compared with wild-type RNF186, suggesting loss of an essential transmembrane domain leads to mislocalization as the protective mechanism. Targeted sequencing, imputation-based genotyping in case-control cohorts, functional characterization of truncated protein expression and subcellular localization Nature communications Medium 27503255
2018 Overexpression of RNF186 in mouse primary hepatocytes induces ER stress, elevating IRE1, CHOP, and phospho-eIF2α levels, which impairs insulin signaling through JNK-mediated phosphorylation of IRS1 and increases proinflammatory cytokines (TNFα, IL-6, MCP1); ER stress inhibitor TUDCA reverses these effects. Adenoviral overexpression in primary mouse hepatocytes, western blot for ER stress and insulin signaling pathway components, TUDCA rescue experiment Cellular signalling Medium 30223017
2019 RNF186 directly binds Sestrin-2 through distinct C-terminal motifs and ubiquitinates Sestrin-2 at Lys-13, targeting it for proteasomal degradation; RNF186 knockdown increases Sestrin-2 protein levels and decreases mTORC1 activation, establishing an RNF186–Sestrin-2 axis in nutrient sensing. siRNA library screen for E3 ligases, co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (K13), western blot for mTORC1 signaling The Journal of biological chemistry High 31586034
2020 RNF186 acts as an E3 ubiquitin ligase for EPHB2 in colonic epithelial cells; upon EFNB1 stimulation, RNF186 ubiquitinates EPHB2 at Lys892, which recruits MAP1LC3B to activate autophagy. Rnf186-/- and Ephb2-/- mice show more severe DSS-induced colitis due to impaired autophagy in colon epithelial cells. Co-immunoprecipitation, in vivo ubiquitination assay with site-directed mutagenesis (K892R), KO mouse DSS colitis model, autophagy flux assay, LC3B recruitment assay Autophagy High 33280498
2020 Forced expression of RNF186 in colorectal cancer cell lines suppresses NF-κB activation by reducing phosphorylation of NF-κB, inhibiting cell growth and migration in vitro and tumor proliferation in vivo; RNF186-/- mice show increased tumor burden in AOM/DSS carcinogenesis model. Overexpression in CRC cell lines, NF-κB phosphorylation assay, in vivo AOM/DSS tumor model, Ki67 immunostaining Cellular signalling Medium 32882406
2021 Upon NOD2 stimulation in human macrophages, RNF186 localizes to the ER, forms a complex with ER stress sensors, and ubiquitinates ATF6 at Lys152, which is required for UPR induction, downstream cytokine secretion, and antimicrobial pathway activation. The IBD risk variant RNF186-A64T shows reduced NOD2-induced ubiquitination and UPR outcomes, which are restored by UPR rescue. RNF186- or ATF6-deficient mice show reduced UPR in colonic tissue and impaired bacterial clearance. Human macrophage transfection, Co-IP with ER stress sensors, in vivo ubiquitination assay, site-directed mutagenesis (K152 on ATF6), KO mouse model with Salmonella and DSS challenge, cytokine assay The Journal of clinical investigation High 34623328
2021 Upon stimulation of multiple PRRs (not only NOD2) in human macrophages, RNF186 promotes ubiquitination of signaling complex molecules shared across PRRs and those unique to select PRRs, and is required for PRR-initiated signaling complex assembly, downstream ROS/RNS, autophagy, and intracellular bacterial clearance. IBD risk variant RNF186-A64T and rs6426833 carrier macrophages show loss-of-function in these PRR-initiated outcomes. Human macrophage KD/OE, ubiquitination assay across multiple PRR stimulations, reactive oxygen/nitrogen species assay, bacterial clearance assay, IBD-risk variant transfection Proceedings of the National Academy of Sciences of the United States of America High 34353900
2022 After TNF stimulation in colorectal epithelial cells, EPHB2 is ubiquitinated by RNF186; ubiquitinated EPHB2 recruits TAB2 and phosphorylates TAB2 at nine tyrosine sites, which is required for TAB2–TAK1 binding and downstream TNF signaling. RNF186-KO cells show defective TNF signaling, and RNF186-KO mice have reduced colitis-associated colorectal tumor burden. Co-immunoprecipitation, ubiquitination assay, phospho-mapping of TAB2 tyrosine sites, KO mouse AOM/DSS tumor model, gain-of-function EPHB2 mutation analysis Journal of immunology High 36130827
2023 RNF186 acts as an E3 ubiquitin ligase for cytoplasmic HMGB1, catalyzing K48- and K63-linked ubiquitination leading to proteasomal degradation of cytoplasmic HMGB1 in hepatocytes. RNF186 depletion stabilizes cytoplasmic HMGB1 (whose nuclear-to-cytoplasmic translocation is induced in NAFLD), thereby promoting lipophagy and reducing lipid accumulation. HMGB1 knockdown reverses the lipophagy activation caused by RNF186 depletion. RNF186 KO mice, primary hepatocyte KD/KO, in vivo ubiquitination assay with linkage-specific antibodies, HMGB1 subcellular fractionation, autophagic flux assay, epistasis by HMGB1 knockdown rescue Metabolism: clinical and experimental High 38158076
2025 In skeletal muscle, RNF186 deficiency reduces ER stress-mediated UPR by preventing ubiquitination of ATF6, leading to increased GLUT4 transcription. RNF186 deficiency also promotes membrane translocation of GLUT4 via the AKT/TBC1D4 signaling pathway. Overexpression of RNF186 decreases AKT signaling and GLUT4 expression. RNF186 KO mice on HFD, in vitro high-glucose skeletal myocyte and hepatocyte models, western blot for ATF6 ubiquitination and UPR markers, GLUT4 immunofluorescence for membrane translocation, AKT/TBC1D4 phosphorylation assay Cell & bioscience Medium 41316307

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS genetics 177 24068945
2020 RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy 52 33280498
2016 Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186. Mucosal immunology 52 27381925
2016 A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nature communications 52 27503255
2020 The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function. International journal of molecular sciences 49 32486221
2013 A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1. Cellular signalling 38 23896122
2021 Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response. The Journal of clinical investigation 31 34623328
2019 The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby controls nutrient sensing. The Journal of biological chemistry 24 31586034
2023 HGF Secreted by Menstrual Blood-Derived Endometrial Stem Cells Ameliorates Non-Alcoholic Fatty Liver Disease Through Downregulation of Hepatic Rnf186. Stem cells (Dayton, Ohio) 21 36573461
2023 Ubiquitination of cytoplasmic HMGB1 by RNF186 regulates hepatic lipophagy in non-alcoholic fatty liver disease. Metabolism: clinical and experimental 19 38158076
2018 RNF186 impairs insulin sensitivity by inducing ER stress in mouse primary hepatocytes. Cellular signalling 16 30223017
2021 The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proceedings of the National Academy of Sciences of the United States of America 14 34353900
2020 The role and mechanism of action of RNF186 in colorectal cancer through negative regulation of NF-κB. Cellular signalling 12 32882406
2022 RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells. Journal of immunology (Baltimore, Md. : 1950) 8 36130827
2022 Deletion of RNF186 expression suppresses diet-induced hepatic steatosis by regulating insulin activity. iScience 6 35198905
2025 RNF186 gene variant and zonulin levels in inflammatory bowel disease: A pilot study. Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology 1 40328563
2025 RNF186 controls glucose metabolism in metabolic dysfunction-associated fatty liver disease. Cell & bioscience 1 41316307
2026 Hsa-miR-10a-5p/RNF186 modulates endoplasmic reticulum stress to exacerbate the development of ulcerative colitis. Biotechnic & histochemistry : official publication of the Biological Stain Commission 0 41510627

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