Science, 25 April, 2024, DOI：https://doi.org/10.1126/science.adm9190

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, And 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. Here 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. Cryo–electron microscopy (cryo-EM) structure illustrates assembly mechanism for the 44-mer TrichoGSDM pore. Second, RCD-1-1/RCD-1-2, encoded by polymorphic rcd-1 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. Cryo-EM structure reveals a pore of 11 RCD-1-1/RCD-1-2 heterodimers and heterodimerization-triggered pore assembly mechanism. This study shows mechanistic diversities in GSDM activation and indicates versatile functions of GSDMs.

Article link：https://www.science.org/doi/10.1126/science.adm9190