Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development
| Autor: | Jing Yang, Seth L. Masters, Pamela Pui Wah Lee, Bing Huang, Zhanghua Chen, Yu-Lung Lau, Lingli Zhou, Xingtian Yang, Liya Xiong, Andrew M. Lew, Fan Bai, Hanquan Liang, Man Luo, Jun Wang, Jun Cui, Daniel Leung, Yan Zhang, Lanlan Geng, Gong Sitang, Yukun Liu, Zhiyao Zhao, Koon Wing Chan, Liping Ye, Tao Liu, Peiyu Chen, Yuxia Zhang, Hongli Wang, Wanling Yang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male THP-1 Cells Biopsy Immunology Mutation Missense Pyrin domain Inflammatory bowel disease Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine Risk Factors NLR Family Pyrin Domain-Containing 3 Protein Exome Sequencing Immunology and Allergy Medicine Animals Humans Age of Onset Acute colitis Mice Knockout Gastrointestinal tract integumentary system Deubiquitinating Enzymes business.industry Pyroptosis Ubiquitination Infant Inflammasome medicine.disease Inflammatory Bowel Diseases 030104 developmental biology HEK293 Cells Amino Acid Substitution 030220 oncology & carcinogenesis Female business Deubiquitination medicine.drug |
| Zdroj: | The Journal of allergy and clinical immunology. 147(1) |
| ISSN: | 1097-6825 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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