Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated autophagy

• Published in: Molecular cell 2023-01, Vol.83 (2), p.281-297.e10
• Main Authors: Wang, Liqiu, Cai, Jing, Zhao, Xin, Ma, Ling, Zeng, Ping, Zhou, Lingli, Liu, Yukun, Yang, Shuai, Cai, Zhe, Zhang, Song, Zhou, Liang, Yang, Jiahui, Liu, Tao, Jin, Shouheng, Cui, Jun
• Format: Article
• Language: English
• Subjects: Acyltransferases; Animals; Autophagy; Chaperone-Mediated Autophagy; inflammasome; Inflammasomes - metabolism; inflammation; Inflammation - chemically induced; Inflammation - genetics; Lipoylation; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; palmitoylation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.12.002

As a key component of the inflammasome, NLRP3 is a critical intracellular danger sensor emerging as an important clinical target in inflammatory diseases. However, little is known about the mechanisms that determine the kinetics of NLRP3 inflammasome stability and activity to ensure effective and controllable inflammatory responses. Here, we show that S-palmitoylation acts as a brake to turn NLRP3 inflammasome off. zDHHC12 is identified as the S-acyltransferase for NLRP3 palmitoylation, which promotes its degradation through the chaperone-mediated autophagy pathway. Zdhhc12 deficiency in mice enhances inflammatory symptoms and lethality following alum-induced peritonitis and LPS-induced endotoxic shock. Notably, several disease-associated mutations in NLRP3 are associated with defective palmitoylation, resulting in overt NLRP3 inflammasome activation. Thus, our findings identify zDHHC12 as a repressor of NLRP3 inflammasome activation and uncover a previously unknown regulatory mechanism by which the inflammasome pathway is tightly controlled by the dynamic palmitoylation of NLRP3. [Display omitted] •Palmitoylation of NLRP3 at C844 is critical for preventing inflammasome activation•zDHHC12 directly palmitoylates NLRP3•zDHHC12 enhances NLRP3 degradation through CMA pathway•Defective NLRP3 palmitoylation is associated with inflammatory diseases NLRP3 is a critical intracellular sensor. However, the mechanism preventing its sustained activation remains obscure. Wang et al. demonstrate that zDHHC12-mediated NLRP3 palmitoylation is essential to turn NLRP3 inflammasome off via promoting its degradation through chaperone-mediated autophagy. Defective NLRP3 palmitoylation is associated with pathological conditions with excessive inflammation.