2. Academic Validation
  3. Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated autophagy

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

  • Mol Cell. 2022 Dec 20;S1097-2765(22)01137-6. doi: 10.1016/j.molcel.2022.12.002.
Liqiu Wang 1,  Jing Cai 1,  Xin Zhao 1,  Ling Ma 1,  Ping Zeng 2,  Lingli Zhou 1,  Yukun Liu 3,  Shuai Yang 1,  Zhe Cai 2,  Song Zhang 2,  Liang Zhou 1,  Jiahui Yang 4,  Tao Liu 1,  Shouheng Jin 1,  Jun Cui 5
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 The Department of Rheumatology, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong, China.
  • 3 Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China.
  • 4 Huizhou Municipal Central Hospital, Huizhou, Guangdong, China.
  • 5 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: [email protected].
PMID: 36586411 DOI: 10.1016/j.molcel.2022.12.002
Abstract

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.

Keywords

NLRP3; chaperone-mediated autophagy; inflammasome; inflammation; palmitoylation.

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