The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis

• DOI: 10.1126/sciimmunol.adn1452
• Publication Date: 2024-03-26T13:59:17Z
• Authors: Arumugam Balasubr...; Alan Y. Hsu; Laxman Ghimire; Muhammad Tahir; Pascal Devant; Pietro Fontana; Gang Du; Xing Liu; Dang Fabin; Hiroto Kambara; Xuemei Xie; Fei Liu; Tomoya Hasegawa; Rong Xu; Hongbo Yu; Mei Chen; Steven Kolakowski; Sunia Trauger; Martin Røssel Larsen; Wenyi Wei; Hao Wu; Jonathan C. Kagan; Judy Lieberman; Hongbo R. Luo
• Keywords: Proteomics; 0301 basic medicine; Mice; 03 medical and health sciences; Gasdermins; Lipoylation; Pyroptosis; Animals; Humans

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys 191 /Cys 192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.