Palmitoylation at a conserved cysteine residue facilitates gasdermin D- mediated pyroptosis and cytokine release

• 成果类型: Article
• 署名作者: Liu, Zhonghua; Li, Sai; Wang, Chuanping; Vidmar, Kaylynn J.; Bracey, Syrena; Li, Ling; Willard, Belinda; Miyagi, Masaru; Lan, Tong; Dickinson, Bryan C.; Osme, Abdullah; Pizarro, Theresa T.; Xiao, Tsan Sam
• 署名单位: University System of Ohio; Case Western Reserve University; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Cleveland Clinic Foundation; University System of Ohio; Case Western Reserve University; University of Chicago; University of Alabama System; University of Alabama Birmingham
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10904
• DOI: 10.1073/pnas.2400883121
• 发表日期: 2024-07-16
• 关键词: protein palmitoylation; cell-death; inflammatory caspases; pore formation; gsdmd; mechanism; localization; inhibition; activation; driven

摘要

Gasdermin D (GSDMD)-- mediated pyroptotic cell death drives inflammatory cytokine release and downstream immune responses upon inflammasome activation, which play important roles in host defense and inflammatory disorders. Upon activation by pro- teases, the GSDMD N-- terminal domain (NTD) undergoes oligomerization and membrane translocation in the presence of lipids to assemble pores. Despite intensive studies, the molecular events underlying the transition of GSDMD from an autoinhibited soluble form to an oligomeric pore form inserted into the membrane remain incompletely understood. Previous work characterized S- palmitoylation for gasdermins from bacteria, fungi, invertebrates, as well as mammalian gasdermin E (GSDME). Here, we report that a conserved residue Cys191 in human GSDMD was S- palmitoylated, which promoted GSDMD-- mediated pyroptosis and cytokine release. Mutation of Cys191 or treatment with palmitoyltransferase inhibitors cyano-- myracrylamide (CMA) or 2-- bromopalmitate (2BP) suppressed GSDMD palmitoylation, its localization to the membrane and dampened pyroptosis or IL- 1f3 f3 secretion. Furthermore, Gsdmd-- dependent inflammatory responses were alleviated by inhibition of palmitoylation in vivo. By contrast, coexpression of GSDMD with palmitoyltransferases enhanced pyroptotic cell death, while introduction of exogenous palmitoylation sequences fully restored pyroptotic activities to the C191A mutant, suggesting that palmitoylation-- mediated membrane localization may be distinct from other molecular events such as GSDMD conformational change during pore assembly. Collectively, our study suggests that S- palmitoylation may be a shared regulatory mechanism for GSDMD and other gasdermins, which points to potential avenues for therapeutically targeting S- palmitoylation of gasdermins in inflammatory disorders.