2. Academic Validation
  3. ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation

ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation

  • J Exp Med. 2021 Sep 6;218(9):e20202637. doi: 10.1084/jem.20202637.
Shuhang Li 1,  Linlin Wang 2,  Zhihao Xu 3,  Yuanyuan Huang 1,  Rufeng Xue 4,  Ting Yue 5,  Linfeng Xu 5,  Fanwu Gong 3,  Shiyu Bai 1,  Qielan Wu 1,  Jiwei Liu 1,  Bolong Lin 3,  Huimin Zhang 1,  Yanhong Xue 2,  Pingyong Xu 2,  Junjie Hou 2,  Xiaofei Yang 6,  Tengchuan Jin 1,  Rongbin Zhou 1,  Jizhong Lou 2,  Tao Xu 2,  Li Bai 1 3
Affiliations

Affiliations

  • 1 Department of Oncology of the First Affiliated Hospital, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 3 Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 4 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 5 School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 6 College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.
PMID: 34342641 DOI: 10.1084/jem.20202637
Abstract

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASCC171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

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