Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development.,Journal of Allergy and Clinical Immunology

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Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-09-15 , DOI: 10.1016/j.jaci.2020.09.003
Lingli Zhou ₁ , Tao Liu ₁ , Bing Huang ₂ , Man Luo ₁ , Zhanghua Chen ₃ , Zhiyao Zhao ₁ , Jun Wang ₁ , Daniel Leung ₄ , Xingtian Yang ₄ , Koon Wing Chan ₄ , Yukun Liu ₁ , Liya Xiong ₁ , Peiyu Chen ₁ , Hongli Wang ₁ , Liping Ye ₁ , Hanquan Liang ₁ , Seth L Masters ₅ , Andrew M Lew ₅ , Sitang Gong ₁ , Fan Bai ₃ , Jing Yang ₄ , Pamela Pui-Wah Lee ₄ , Wanling Yang ₄ , Yan Zhang ₁ , Yu-Lung Lau ₄ , Lanlan Geng ₁ , Yuxia Zhang ₁ , Jun Cui ₁

Affiliation

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.

中文翻译：

过度的NLRP3-R779C变体去泛素化有助于非常早发的炎症性肠病的发展。

背景

早发性炎症性肠病（VEOIBD）是在婴儿期或儿童早期期间发生的胃肠道慢性炎症性疾病。NOD样受体家族，含有3个（NLRP3）炎性小体的吡啶结构域已成为肠道稳态的关键调节因子。但是，NLRP3变体是否可能改变VEIBDD风险尚不清楚。

目的

我们试图调查在3名有胃肠道症状的患者中发现的罕见NLRP3变体是否以及如何促进VEOIBD的发展。

方法

进行了全外显子组测序和生物信息学分析，以筛选VEOIBD患儿队列中与疾病相关的NLRP3变异。在具有NLRP3炎性体成分，强力霉素诱导的NLRP3巨噬细胞以及来自NLRP3变异患者的PBMC和活检组织中，在重组的HEK293T人胚肾细胞中测定了炎性体激活。使用硫酸葡聚糖钠诱导的急性结肠炎模型确定变体的发病机理。

结果

我们在3例有胃肠道症状的患者中鉴定了由rs772009059（R779C）编码的NLRP3的主要功能增强错义变体。功能分析表明，R779C增加了巨噬细胞中的NLRP3炎性体激活和焦磷酸化。这是通过与在髓样细胞中高度表达的去泛素化酶BRCC3和JOSD2结合而增强的NLRP3的去泛素化介导的。在硫酸葡聚糖钠诱导的急性结肠炎模型中，造血细胞中的NLRP3-R779C导致更严重的结肠炎，可通过敲低BRCC3或JOSD2来缓解。