#DAPI (Hydrochloride); #2879038
Nat Chem Biol. 2024 Feb 27
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 Wang 12, Pengyan Xia 13 14 15
Affiliations expand
- 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.