Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development - 09/01/21
, Lanlan Geng, MD a, ⁎ , Yuxia Zhang, PhD a, ⁎ , Jun Cui, PhD a, ⁎ Abstract |
Background |
Very-early-onset inflammatory bowel disease (VEOIBD) is a chronic inflammatory disease of the gastrointestinal tract occurring during infancy or early childhood. NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has emerged as a crucial regulator of intestinal homeostasis; however, whether NLRP3 variants may modify VEOIBD risk is unknown.
Objective |
We sought to investigate whether and how a rare NLRP3 variant, found in 3 patients with gastrointestinal symptoms, contributes to VEOIBD development.
Methods |
Whole-exome sequencing 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 human embryonic kidney 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 dextran sulfate sodium–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 dextran sulfate sodium–induced acute colitis model, NLRP3-R779C in hematopoietic cells resulted in more severe colitis, which can be ameliorated via knockdown of BRCC3 or JOSD2.
Conclusions |
BRCC3 and JOSD2 mediate NLRP3-R779C deubiquitination, which promotes NLRP3 inflammasome activation and the risk of developing VEOIBD.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : NLRP3, VEOIBD, deubiquitinase, JOSD2, BRCC3
Abbreviations used : BM, DSS, DUB, GI, IBD, KO, LRR, NLRP3, VEOIBD, WT
Mappa
| This work was supported by the National Natural Science Foundation of China (grant nos. 31870862, 31770978, 91742109, and 81873869), The Society for the Relief of Disabled Children, Innovation and Technology Fund, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region (ITS/417/18), the Fundamental Research Funds for the Central Universities (19lgpy198), and the National Health and Medical Research Council of Australia (grant nos. 1143976, 1150425, and 1080321). S.L.M. acknowledges funding from The Sylvia and Charles Viertel Foundation and HHMI-Wellcome International Research Scholarship. |
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| Disclosure of potential conflict of interest: S. L. Masters is a scientific advisor for IFM therapeutics. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 1
P. 267-279 - Gennaio 2021 Ritorno al numero
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