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

TitleExcessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development
Authors
KeywordsNLRP3
VEOIBD
deubiquitinase
JOSD2
BRCC3
Issue Date2021
PublisherMosby, Inc. The Journal's web site is located at http://www.elsevier.com/locate/jaci
Citation
Journal of Allergy and Clinical Immunology, 2021, v. 147 n. 1, p. 267-279 How to Cite?
AbstractBackground: 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.
Persistent Identifierhttp://hdl.handle.net/10722/295357
ISSN
2020 Impact Factor: 10.793
2020 SCImago Journal Rankings: 3.281
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhou, L-
dc.contributor.authorLiu, T-
dc.contributor.authorHuang, B-
dc.contributor.authorLuo, M-
dc.contributor.authorChen, Z-
dc.contributor.authorZhao, Z-
dc.contributor.authorWang, J-
dc.contributor.authorLEUNG, D-
dc.contributor.authorYANG, X-
dc.contributor.authorChan, KW-
dc.contributor.authorLiu, Y-
dc.contributor.authorXiong, L-
dc.contributor.authorChen, P-
dc.contributor.authorWang, H-
dc.contributor.authorYe, L-
dc.contributor.authorLiang, H-
dc.contributor.authorMasters, SL-
dc.contributor.authorLew, AM-
dc.contributor.authorGong, S-
dc.contributor.authorBai, F-
dc.contributor.authorYang, J-
dc.contributor.authorLee, PPW-
dc.contributor.authorYang, W-
dc.contributor.authorZhang, Y-
dc.contributor.authorLau, YL-
dc.contributor.authorGeng, L-
dc.contributor.authorZhang, Y-
dc.contributor.authorCui, J-
dc.date.accessioned2021-01-11T13:58:57Z-
dc.date.available2021-01-11T13:58:57Z-
dc.date.issued2021-
dc.identifier.citationJournal of Allergy and Clinical Immunology, 2021, v. 147 n. 1, p. 267-279-
dc.identifier.issn0091-6749-
dc.identifier.urihttp://hdl.handle.net/10722/295357-
dc.description.abstractBackground: 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.-
dc.languageeng-
dc.publisherMosby, Inc. The Journal's web site is located at http://www.elsevier.com/locate/jaci-
dc.relation.ispartofJournal of Allergy and Clinical Immunology-
dc.subjectNLRP3-
dc.subjectVEOIBD-
dc.subjectdeubiquitinase-
dc.subjectJOSD2-
dc.subjectBRCC3-
dc.titleExcessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development-
dc.typeArticle-
dc.identifier.emailChan, KW: kwchan@hku.hk-
dc.identifier.emailYang, J: jingy09@hku.hk-
dc.identifier.emailLee, PPW: ppwlee@hku.hk-
dc.identifier.emailYang, W: yangwl@hku.hk-
dc.identifier.emailLau, YL: lauylung@hku.hk-
dc.identifier.authorityLee, PPW=rp00462-
dc.identifier.authorityYang, W=rp00524-
dc.identifier.authorityLau, YL=rp00361-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jaci.2020.09.003-
dc.identifier.pmid32941940-
dc.identifier.scopuseid_2-s2.0-85092255718-
dc.identifier.hkuros320877-
dc.identifier.volume147-
dc.identifier.issue1-
dc.identifier.spage267-
dc.identifier.epage279-
dc.identifier.isiWOS:000607781700002-
dc.publisher.placeUnited States-

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