S-Palmitoylation of Gasdermin D: A Key Regulator of Membrane Translocation and Pyroptosis Activation 9067

Abstract Description Plasma membrane perforation by the gasdermin D N-terminal domain (GSDMD-NT), activated through caspase cleavage, triggers pyroptosis. While GSDMD-NT pore formation is known, its membrane translocation and activation mechanisms are less understood. Fatty acid synthase (FASN) was identified as a GSDMD-binding partner, and S-palmitoylation at cysteine residues Cys191 in humans and Cys192 in mice, catalyzed by ZDHHC5 and ZDHHC9 and enhanced by ROS, was shown to mediate GSDMD-NT translocation but not the full-length protein. Pre-inflammasome activation palmitoylation of GSDMD-FL, induced by stimuli like LPS, primes macrophages for pyroptosis. Inhibiting GSDMD palmitoylation reduced macrophage pyroptosis, IL-1β release, organ damage, and improved survival in septic mice. These findings establish GSDMD-NT palmitoylation as a key regulatory mechanism and a promising target for therapeutic strategies in infectious and inflammatory diseases, including sepsis. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)