研究人员报告了两种不依赖于切割的gasdermin（GSDM）激活方式。首先，TrichoGSDM是一种来自基础后生生物Trichoplax adhaerens的仅有孔形成域的蛋白质，是一种二硫键连接的自抑制二聚体，通过还原二硫键而激活。冷冻电子显微镜（cryo-EM）结构显示了44聚合体TrichoGSDM孔的组装机制。其次，由丝状真菌Neurospora crassa中的多态rcd-1编码的RCD-1-1/RCD-1-2也是只孔形成域的GSDM。
当RCD-1-1和RCD-1-2相遇时，会成孔并引起焦亡，这也是链孢霉中同种异体识别的基础。cryo-EM结构揭示了由11个RCD-1-1/RCD-1-2异源二聚体组成的孔和异源二聚体触发的孔组装机制。这项研究显示了GSDM激活机制的多样性，并表明了GSDM的多功能性。
据了解，GSDM是一种成孔的蛋白质，可执行焦亡以进行免疫防御。GSDM是双结构域蛋白，通过蛋白水解去除抑制结构域来激活。
附：英文原文
Title: Cleavage-independent activation of ancient eukaryotic gasdermins and structural mechanisms
Author: Yueyue Li, Yanjie Hou, Qi Sun, Huan Zeng, Fanyi Meng, Xiang Tian, Qun He, Feng Shao, Jingjin Ding
Issue&Volume: 2024-04-25
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.
DOI: adm9190
Source: https://www.science.org/doi/10.1126/science.adm9190