ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D

Gang Du (), Liam B. Healy, Liron David (), Caitlin Walker, Tarick J. El-Baba, Corinne A. Lutomski, Byoungsook Goh, Bowen Gu, Xiong Pi, Pascal Devant, Pietro Fontana, Ying Dong, Xiyu Ma, Rui Miao, Arumugam Balasubramanian, Robbins Puthenveetil, Anirban Banerjee, Hongbo R. Luo, Jonathan C. Kagan, Sungwhan F. Oh, Carol V. Robinson, Judy Lieberman and Hao Wu ()
Additional contact information
Gang Du: Harvard Medical School
Liam B. Healy: Harvard Medical School
Liron David: Harvard Medical School
Caitlin Walker: Harvard Medical School
Tarick J. El-Baba: University of Oxford
Corinne A. Lutomski: University of Oxford
Byoungsook Goh: Brigham and Women’s Hospital
Bowen Gu: Boston Children’s Hospital
Xiong Pi: Harvard Medical School
Pascal Devant: Boston Children’s Hospital
Pietro Fontana: Harvard Medical School
Ying Dong: Harvard Medical School
Xiyu Ma: Boston Children’s Hospital
Rui Miao: Boston Children’s Hospital
Arumugam Balasubramanian: Harvard Medical School
Robbins Puthenveetil: National Institutes of Health
Anirban Banerjee: National Institutes of Health
Hongbo R. Luo: Harvard Medical School
Jonathan C. Kagan: Boston Children’s Hospital
Sungwhan F. Oh: Brigham and Women’s Hospital
Carol V. Robinson: University of Oxford
Judy Lieberman: Boston Children’s Hospital
Hao Wu: Harvard Medical School

Nature, 2024, vol. 630, issue 8016, 437-446

Abstract: Abstract Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores after cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1–10. Here we report that GSDMD Cys191 is S-palmitoylated and that palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Cleavage-deficient GSDMD (D275A) is also palmitoylated after inflammasome stimulation or treatment with ROS activators and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. ZDHHC5 and ZDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated at their N termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that functions as a general switch for the activation of this pore-forming family.

Date: 2024
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DOI: 10.1038/s41586-024-07373-5

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