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. 2024 Jun;630(8016):437-446.
doi: 10.1038/s41586-024-07373-5. Epub 2024 Apr 10.

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

Gang Du #  1   2 , Liam B Healy #  3   4 , Liron David  5   6   7 , Caitlin Walker  3   4   8 , Tarick J El-Baba  9   10 , Corinne A Lutomski  9   10 , Byoungsook Goh  11 , Bowen Gu  4   12 , Xiong Pi  3   4 , Pascal Devant  13 , Pietro Fontana  3   4 , Ying Dong  3   4 , Xiyu Ma  4   12 , Rui Miao  4   12 , Arumugam Balasubramanian  14   15 , Robbins Puthenveetil  16 , Anirban Banerjee  16 , Hongbo R Luo  14   15 , Jonathan C Kagan  13 , Sungwhan F Oh  11 , Carol V Robinson  9   10 , Judy Lieberman  4   12 , Hao Wu  17   18
Affiliations

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

Gang Du et al. Nature. 2024 Jun.

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.

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Conflict of interest statement

Competing interests H.W. and J.L. are cofounders of Ventus Therapeutics. J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, MindImmune Therapeutics and Neumora Therapeutics. None of these relationships impacted this study. The other authors declare no competing interests.

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