2. Academic Validation
  3. FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system

  • Cell Death Differ. 2022 Sep 14. doi: 10.1038/s41418-022-01054-4.
Yangyang Zhu  # 1 2,  Hao Zhang  # 1 2,  Huawei Mao  # 3,  Suqin Zhong 1 2,  Yubing Huang 2,  Sirong Chen 2,  Kai Yan 4,  Zhibin Zhao 4,  Xiaohan Hao 2,  Yue Zhang 3,  Han Yao 5,  Xiaowan Huang 2,  Meimei Wang 1 2,  Wenbin Zhang 2,  Juan Li 6,  Guangxun Meng 6,  Xiaohua Qin 1 2,  Zhiming Ye 4,  Jiani Shen 4,  Yang Song 1 2,  Youcui Xu 4,  Zhenyu Yang 7,  Liansheng Wang 8 9,  Yunjiao Zhang 10,  Longping Wen 11 12
Affiliations

Affiliations

  • 1 Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
  • 2 School of Medicine & Institute for Life Sciences, South China University of Technology, Guangzhou, China.
  • 3 Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing, China.
  • 4 Department of Nephrology, Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 5 Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology& Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
  • 7 China-Singapore International Joint Research Institute, Guangzhou, China.
  • 8 Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. wangliansheng@gdph.org.cn.
  • 9 Department of Nephrology, Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China. wangliansheng@gdph.org.cn.
  • 10 School of Medicine & Institute for Life Sciences, South China University of Technology, Guangzhou, China. zhangyunjiao@scut.edu.cn.
  • 11 Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. lpwen@ustc.edu.cn.
  • 12 Department of Nephrology, Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China. lpwen@ustc.edu.cn.
  • # Contributed equally.
PMID: 36104448 DOI: 10.1038/s41418-022-01054-4
Abstract

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane Enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective Autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

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