Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development

BackgroundVery-early-onset inflammatory bowel disease (VEOIBD) is a chronic of the gastrointestinal tract occurring during infancy or early childhood. NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has emerged as crucial regulator intestinal homeostasis; however, whether NLRP3 variants may modify VEOIBD risk unknown.ObjectiveWe sought to investigate and how rare variant, found in patients with symptoms, contributes development.MethodsWhole-exome sequencing bioinformatic analysis were performed screen disease-associated from cohort children VEOIBD. Inflammasome activation was determined reconstituted HEK293T human embryonic kidney cells components, doxycycline-inducible macrophages, well PBMCs biopsies variants. Pathogenesis using dextran sulfate sodium–induced acute colitis model.ResultsWe identified dominant gain-of-function missense variant NLRP3, encoded by rs772009059 (R779C), symptoms. Functional revealed that R779C increased pyroptosis macrophages. This mediated enhanced deubiquitination via binding deubiquitinases BRCC3 JOSD2, which are highly expressed myeloid cells. In model, NLRP3-R779C hematopoietic resulted more severe colitis, can be ameliorated knockdown JOSD2.ConclusionsBRCC3 JOSD2 mediate deubiquitination, promotes developing Very-early-onset unknown. We development. Whole-exome model. JOSD2.