Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development
Journal Title
Journal of Allergy and Clinical Immunology
Publication Type
Journal epub ahead of print
BACKGROUND: Very-early-onset inflammatory bowel disease (VEOIBD) is a chronic inflammatory disease of the gastrointestinal tract occurring during infancy or early childhood. NLRP3 inflammasome has emerged as a crucial regulator of intestinal homeostasis; however, whether NLRP3 variants may modify VEOIBD risk is unknown. OBJECTIVE: To investigate whether and how a rare NLRP3 variant, found in 3 patients with gastrointestinal symptoms, contributes to VEOIBD development. METHODS: Whole exome sequencing (WES) and bioinformatic analysis were performed to screen disease-associated NLRP3 variants from a cohort of children with VEOIBD. Inflammasome activation was determined in reconstituted HEK293T cells with NLRP3 inflammasome components, doxycycline-inducible NLRP3 macrophages, as well as PBMCs and biopsies from patients with NLRP3 variants. Pathogenesis of the variants was determined using a DSS-induced acute colitis model. RESULTS: We identified a dominant gain-of-function missense variant of NLRP3, encoded by rs772009059 (R779C), in 3 patients with gastrointestinal symptoms. Functional analysis revealed that R779C increased NLRP3 inflammasome activation and pyroptosis in macrophages. This was mediated by enhanced deubiquitination of NLRP3 via binding with deubiquitinases BRCC3 and JOSD2, which are highly expressed in myeloid cells. In a DSS-induced acute colitis model, NLRP3-R779C in hematopoietic cells resulted in more severe colitis, which can be ameliorated via knockdown of BRCC3 or JOSD2. CONCLUSION: BRCC3 and JOSD2 mediate NLRP3-R779C deubiquitination, which promotes NLRP3 inflammasome activation and the risk of developing VEOIBD.
WEHI Research Division(s)
Inflammation; Immunology
PubMed ID
NHMRC Grants
NHMRC/1143976 NHMRC/1150425 NHMRC/1080321
Rights Notice
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Creation Date: 2020-10-02 10:27:59
Last Modified: 2020-10-02 10:30:33
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