Cleavage-independent activation of ancient eukaryotic gasdermins and structural mechanisms
Yueyue Li, Yanjie Hou, Qi Sun, Huan Zeng, Fanyi Meng, Xiang Tian, Qun He, Feng Shao, Jingjin Ding
Abstract
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, Tricho GSDM, 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 Tricho GSDM 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.