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

  • Sci Immunol. 2024 Apr 12;9(94):eadn1452. doi: 10.1126/sciimmunol.adn1452.
Arumugam Balasubramanian  1 ,  Alan Y Hsu  1 ,  Laxman Ghimire  1 ,  Muhammad Tahir  1  2 ,  Pascal Devant  3 ,  Pietro Fontana  4 ,  Gang Du  4 ,  Xing Liu  5 ,  Dang Fabin  6 ,  Hiroto Kambara  1 ,  Xuemei Xie  1 ,  Fei Liu  1 ,  Tomoya Hasegawa  1 ,  Rong Xu  1 ,  Hongbo Yu  7 ,  Mei Chen  8 ,  Steven Kolakowski  8 ,  Sunia Trauger  8 ,  Martin Røssel Larsen  2 ,  Wenyi Wei  6 ,  Hao Wu  4 ,  Jonathan C Kagan  3 ,  Judy Lieberman  5 ,  Hongbo R Luo  1
Affiliations
  • 1. Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School and Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 811, Boston, MA 02115, USA.
  • 2. Biomedical Mass Spectrometry and Systems Biology, University of Southern Denmark, Odense, Denmark.
  • 3. Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 5. Department of Pediatrics, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 6. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 7. Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132, USA.
  • 8. Harvard Center for Mass Spectrometry, Harvard University, Boston, MA 02115, USA.
PMID: 38530158 DOI: 10.1126/sciimmunol.adn1452
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.