{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genomic studies in ulcerative colitis have identified RNF186 as a key modulator of disease risk. Rare non‐synonymous variants and a protein‐truncating allele in RNF186 have been associated with changes in susceptibility to ulcerative colitis, where mutations in its ubiquitin ligase domain confer a moderate risk, and a specific truncating variant (p.R179X) has been found to be protective. These genetic findings underscore RNF186’s importance in intestinal inflammation and immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, RNF186 encodes a RING finger E3 ubiquitin ligase characterized by two transmembrane domains and predominant localization to the endoplasmic reticulum. Functional studies demonstrate that RNF186 directs ER stress-mediated apoptosis by ubiquitinating substrates such as BNip1, thereby modulating the unfolded protein response. In parallel, RNF186 regulates nutrient sensing by targeting Sestrin-2 for ubiquitination, which in turn impacts mTORC1 activity. Furthermore, comprehensive reviews of tissue-specific RNF ubiquitin ligases place RNF186 within a broader context of proteins involved in inflammatory and stress responses across several organ systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in stress and metabolic signaling, RNF186 is pivotal for innate immune function. It mediates the ubiquitination of ATF6 to facilitate proper engagement of the unfolded protein response during pattern recognition receptor signaling, thereby influencing cytokine secretion and antimicrobial pathways. Moreover, RNF186 contributes to optimal assembly of downstream signaling complexes required for effective bacterial clearance. In the context of cancer biology, overexpression of RNF186 suppresses NF-κB activation and tumor cell proliferation in colorectal cancer, and recent pan-cancer analyses suggest that its expression levels and activity may have wider prognostic and therapeutic implications across malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mélissa Beaudoin, Philippe Goyette, Gabrielle Boucher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003723"}], "href": "https://doi.org/10.1371/journal.pgen.1003723"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24068945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24068945"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Manuel A Rivas, Daniel Graham, Patrick Sulem, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2013.07.016"}], "href": "https://doi.org/10.1016/j.cellsig.2013.07.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23896122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23896122"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Takumi Okamoto, Kazunori Imaizumi, Masayuki Kaneko "}, {"type": "b", "children": [{"type": "t", "text": "The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21113921"}], "href": "https://doi.org/10.3390/ijms21113921"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32486221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32486221"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Travis B Lear, Karina C Lockwood, Yurong Ouyang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby controls nutrient sensing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.AC119.010671"}], "href": "https://doi.org/10.1074/jbc.AC119.010671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31586034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31586034"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kishu Ranjan, Matija Hedl, Saloni Sinha, et al. 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