Work

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

Year: 2025

Type: article

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)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2521

Authors: Arumugam Balasubramanian, Hongbo R. Luo

Institution: Brigham and Women's Hospital

Language: English

Topic: Inflammasome and immune disorders

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

OpenAlex ID: W4416451254