ArticleThe Journal of clinical investigation2021
Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 34 citations in OpenAlex.
- Hepatic PDIA5 improves hyperglycaemia and insulin resistance through stabilisation of ATF6.Diabetologia · 2026Article
- Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.The FEBS journal · 2026Review
- OTOP2 proton channel couples luminal pH sensing to intestinal immune homeostasis.The Journal of biological chemistry · 2026Article
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Activating transcription factors: Orchestrators of macrophage biology in pathological settings (Review).International journal of molecular medicine · 2026Review
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Ubiquitin-Modifying Enzymes as Cell-Fate Regulators in Intestinal Inflammation.International journal of biological sciences · 2026Review
- Comprehensive Bioinformatics Analysis and Experimental Verification RNF186 Is a Recurrence Signature Gene of Hepatocellular Carcinoma that Promotes Cell Proliferation.Oncology research · 2026Article
- Review
- Isoallolithocholic acid ameliorates intestinal inflammation via metabolically reprogrammed macrophages.Communications biology · 2025Article
- RNF186 controls glucose metabolism in metabolic dysfunction-associated fatty liver disease.Cell & bioscience · 2025Article
- Intestinal Epithelial-Derived USP13 Alleviates Colonic Inflammation by Suppressing GRP78-mediated Endoplasmic Reticulum Stress.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Spatial transcriptomics delineates potential differences in intestinal phenotypes of cardiac and classical necrotizing enterocolitis.iScience · 2025Article
- Advances in predicting breast cancer driver mutations: Tools for precision oncology (Review).International journal of molecular medicine · 2025Review
- Characterization of the Ubiquitin-Modified Proteome of Recombinant Chinese Hamster Ovary Cells in Response to Endoplasmic Reticulum Stress.Biotechnology journal · 2024Article
- Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation.International journal of molecular sciences · 2024Review
- The ubiquitin codes in cellular stress responses.Protein & cell · 2024Review
- Loss of Mptx2 alters bacteria composition and intestinal homeostasis potentially by impairing autophagy.Communications biology · 2024Article
- Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.Gut microbes · 2023Article
- Microbial sensing in the intestine.Protein & cell · 2023Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.
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