ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.

Shuai Yang, Mengqiu Li, Guangyu Lian, Yaoxing Wu, Jun Cui, Liqiu Wang
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Abstract

The NLRP3 inflammasome is a multiprotein complex that plays a vital role in the innate immune system in response to microbial infections and endogenous danger signals. Aberrant activation of the NLRP3 inflammasome is implicated in a spectrum of inflammatory and autoimmune diseases, emphasizing the necessity for precise regulation of the NLRP3 inflammasome to maintain immune homeostasis. The protein level of NLRP3 is a limiting step for inflammasome activation, which must be tightly controlled to avoid detrimental consequences. Here, we demonstrate that ABHD8, a member of the α/β-hydrolase domain-containing (ABHD) family, interacts with NLRP3 and promotes its degradation through the chaperone-mediated autophagy (CMA) pathway. ABHD8 acts as a scaffold to recruit palmitoyltransferase ZDHHC12 to NLRP3 for its palmitoylation as well as subsequent CMA-mediated degradation. Notably, ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. We further confirm that ABHD8 overexpression ameliorates LPS- or alum-triggered NLRP3 inflammasome activation in vivo. Interestingly, the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the ABHD8-NLRP3 association, resulting in an elevation in NLRP3 protein level and excessive inflammasome activation. These findings demonstrate that ABHD8 May represent a potential therapeutic target in conditions associated with NLRP3 inflammasome dysregulation.Abbreviations: 3-MA: 3-methyladenine; ABHD: α/β-hydrolase domain-containing; BMDMs: Bone marrow-derived macrophages; CFZ: carfilzomib; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DAMPs: danger/damage-associated molecular patterns; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; NH4Cl: ammonium chloride; NLRP3: NLR family pyrin domain containing 3; PAMPs: pathogen-associated molecular patterns; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

ABHD8 通过促进伴侣介导的 NLRP3 自噬降解来拮抗炎症。
NLRP3 炎性体是一种多蛋白复合物,在先天性免疫系统中对微生物感染和内源性危险信号起着至关重要的作用。NLRP3 炎症小体的异常激活与一系列炎症和自身免疫性疾病有关,这强调了精确调节 NLRP3 炎症小体以维持免疫平衡的必要性。NLRP3 蛋白水平是炎性体激活的一个限制步骤,必须加以严格控制以避免有害后果。在这里,我们证明了α/β-含水解酶结构域(ABHD)家族成员ABHD8与NLRP3相互作用,并通过伴侣介导的自噬(CMA)途径促进其降解。ABHD8 是一种支架,可将棕榈酰基转移酶 ZDHHC12 招募到 NLRP3 上,使其发生棕榈酰化,并随后通过 CMA 介导降解。值得注意的是,ABHD8 缺乏会导致 NLRP3 蛋白的稳定,并促进 NLRP3 炎性体的激活。我们进一步证实,ABHD8的过表达可改善体内LPS或明矾诱导的NLRP3炎性体活化。有趣的是,严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)的核壳(N)蛋白会损害ABHD8与NLRP3的关联,导致NLRP3蛋白水平升高和炎性体过度激活。这些研究结果表明,在与 NLRP3 炎症小体失调相关的疾病中,ABHD8 可能是一个潜在的治疗靶点:缩写:3-MA:3-甲基腺嘌呤;ABHD:含α/β-水解酶结构域;BMDMs:CFZ:卡非佐米;CHX:环己亚胺;CMA:伴侣介导的自噬;CQ:氯喹;DAMPs:危险/损伤相关分子模式;HSPA8/HSC70:热休克蛋白家族 A(Hsp70)成员 8;LAMP2A:溶酶体相关膜蛋白 2:NH4Cl:氯化铵;NLRP3:NLR 家族含吡咯啉结构域 3;PAMPs:病原体相关分子模式;SARS-CoV-2:严重急性呼吸系统综合征冠状病毒 2。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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