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- Title
The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.
- Authors
Balasubramanian, Arumugam; Hsu, Alan Y.; Ghimire, Laxman; Tahir, Muhammad; Devant, Pascal; Fontana, Pietro; Du, Gang; Liu, Xing; Fabin, Dang; Kambara, Hiroto; Xie, Xuemei; Liu, Fei; Hasegawa, Tomoya; Xu, Rong; Yu, Hongbo; Chen, Mei; Kolakowski, Steven; Trauger, Sunia; Larsen, Martin Røssel; Wei, Wenyi
- Abstract
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 Cys191/Cys192 (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. Editor's summary: Pyroptosis is an inflammatory form of cell death in which certain pathogen-associated molecular patterns trigger the caspase-mediated cleavage gasdermin D (GSDMD), whose N-terminal fragments (GSDMD-NT) rapidly assemble into large transmembrane pores. These pores preferentially release inflammatory cytokines and kill cells by disrupting their electrochemical gradient. Balasubramanian et al. report that the reactive oxygen species–driven palmitoylation of GSDMD-NT (but not full-length GSDMD) at Cys191/Cys192 is required for its translocation to the membrane. Moreover, palmostatin B, a small-molecule inhibitor of GSDMD palmitoylation, suppressed macrophage pyroptosis and tissue damage and enhanced survival in a mouse model of sepsis. Thus, GSDMD palmitoylation is an important and highly regulated checkpoint for pyroptosis, which serves as a crucial nexus between GSDMD cleavage and pore formation. —Seth Thomas Scanlon
- Subjects
FATTY acid synthases; PALMITOYLATION; PYROPTOSIS; REACTIVE oxygen species; CELL death
- Publication
Science Immunology, 2024, Vol 9, Issue 94, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adn1452