Cleavage-independent activation of ancient eukaryotic gasdermins and structural mechanisms

• 成果类型: Article
• 署名作者: Li, Yueyue; Hou, Yanjie; Sun, Qi; Zeng, Huan; Meng, Fanyi; Tian, Xiang; He, Qun; Shao, Feng; Ding, Jingjin
• 署名单位: Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; National Institute of Biological Sciences, Beijing; China Agricultural University; National Institute of Biological Sciences, Beijing; Chinese Academy of Medical Sciences - Peking Union Medical College; Changping Laboratory; Tsinghua University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9602
• DOI: 10.1126/science.adm9190
• 发表日期: 2024-05-17
• 关键词: cryo-em; cell-death; inflammatory caspases; neurospora-crassa; pore formation; gsdmd; pyroptosis; expression

摘要

Gasdermins (GSDMs) are pore-forming proteins that execute pyroptosis for immune defense. GSDMs are two-domain proteins activated by proteolytic removal of the inhibitory domain. In this work, we report two types of cleavage-independent GSDM activation. First, TrichoGSDM, a pore-forming domain-only protein from the basal metazoan Trichoplax adhaerens, is a disulfides-linked autoinhibited dimer activated by reduction of the disulfides. The cryo-electron microscopy (cryo-EM) structure illustrates the assembly mechanism for the 44-mer TrichoGSDM pore. Second, RCD-1-1 and RCD-1-2, encoded by the polymorphic regulator of cell death-1 (rcd-1) gene in filamentous fungus Neurospora crassa, are also pore-forming domain-only GSDMs. RCD-1-1 and RCD-1-2, when encountering each other, form pores and cause pyroptosis, underlying allorecognition in Neurospora. The cryo-EM structure reveals a pore of 11 RCD-1-1/RCD-1-2 heterodimers and a heterodimerization-triggered pore assembly mechanism. This study shows mechanistic diversities in GSDM activation and indicates versatile functions of GSDMs.