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

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, <i>ABHD8</i> 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 <i>in vivo</i>. 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.<b>Abbreviations:</b> 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.