Adipose triglyceride lipase suppresses noncanonical inflammasome by hydrolyzing LPS

Weitao Li; Qiannv Liu; Yan Qian; Chunlei Wang; Chun Kong; Liangliang Sun; Li Sun; Hongwei Liu; Yan Zhang; Dong Jiang; Changtao Jiang; Shuo Wang; Pengyan Xia

doi:10.1038/s41589-024-01569-6

Adipose triglyceride lipase suppresses noncanonical inflammasome by hydrolyzing LPS

Nat Chem Biol. 2024 Feb 27. doi: 10.1038/s41589-024-01569-6. Online ahead of print.

Authors

Weitao Li^#^{1

2

3}, Qiannv Liu^#^{1

2

3}, Yan Qian^{1

2

3}, Chunlei Wang^{1

2

3}, Chun Kong^{1

2

3}, Liangliang Sun^{1

2

3}, Li Sun^{4

5}, Hongwei Liu^{4

5}, Yan Zhang^{1

2

3}, Dong Jiang^{6

7}, Changtao Jiang^{8

9

10

11}, Shuo Wang¹², Pengyan Xia^{13

14

15}

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
² NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
³ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China.
⁴ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
⁵ Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
⁶ Department of Sports Medicine, Peking University Third Hospital, Beijing, China.
⁷ Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, Beijing, China.
⁸ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
⁹ Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China.
¹⁰ Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China.
¹¹ State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
¹² CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
¹³ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China. xiap@pku.edu.cn.
¹⁴ NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China. xiap@pku.edu.cn.
¹⁵ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China. xiap@pku.edu.cn.

^# Contributed equally.

PMID: 38413746
DOI: 10.1038/s41589-024-01569-6

Abstract

Intracellular recognition of lipopolysaccharide (LPS) by mouse caspase-11 or human caspase-4 is a vital event for the activation of the noncanonical inflammasome. Whether negative regulators are involved in intracellular LPS sensing is still elusive. Here we show that adipose triglyceride lipase (ATGL) is a negative regulator of the noncanonical inflammasome. Through screening for genes participating in the noncanonical inflammasome, ATGL is identified as a negative player for intracellular LPS signaling. ATGL binds LPS and catalyzes the removal of the acylated side chains that contain ester bonds. LPS with under-acylated side chains no longer activates the inflammatory caspases. Cells with ATGL deficiency exhibit enhanced immune responses when encountering intracellular LPS, including an elevated secretion of interleukin-1β, decreased cell viability and increased cell cytotoxicity. Moreover, ATGL-deficient mice show exacerbated responses to endotoxin challenges. Our results uncover that ATGL degrades cytosolic LPS to suppress noncanonical inflammasome activation.

Abstract

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