Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA.
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106 USA.
Immunity. 2019 Jul 16;51(1):43-49.e4. doi: 10.1016/j.immuni.2019.04.017. Epub 2019 May 13.
Gasdermin D (GSDMD) is an effector molecule for pyroptosis downstream of canonical and noncanonical inflammasome signaling pathways. Cleavage of GSDMD by inflammatory caspases triggers the oligomerization and lipid binding by its N-terminal domain, which assembles membrane pores, whereas its C-terminal domain binds the N-terminal domain to inhibit pyroptosis. Despite recent progress in our understanding of the structure and function of the murine gasdermin A3 (mGSDMA3), the molecular mechanisms of GSDMD activation and regulation remain poorly characterized. Here, we report the crystal structures of the full-length murine and human GSDMDs, which reveal the architecture of the GSDMD N-terminal domains and demonstrate distinct and common features of autoinhibition among gasdermin family members utilizing their β1-β2 loops. Disruption of the intramolecular domain interface enhanced pyroptosis, whereas mutations at the predicted lipid-binding or oligomerization surface reduced cytolysis. Our study provides a framework for understanding the autoinhibition, lipid binding, and oligomerization of GSDMD by using overlapping interfaces.
Gasdermin D (GSDMD) 是经典和非经典炎性体信号通路下游细胞焦亡的效应分子。炎性半胱天冬酶对 GSDMD 的切割触发其 N 端结构域的寡聚化和脂质结合，从而组装膜孔，而其 C 端结构域结合 N 端结构域以抑制细胞焦亡。尽管我们对鼠源 GSDMA3 的结构和功能有了最新的了解，但 GSDMD 的激活和调节的分子机制仍知之甚少。在这里，我们报告了全长鼠源和人源 GSDMD 的晶体结构，揭示了 GSDMD N 端结构域的结构，并利用其 β1-β2 环展示了不同家族成员间自动抑制的独特和共性特征。破坏分子内结构域界面增强了细胞焦亡，而在预测的脂质结合或寡聚化表面的突变则减少了细胞溶解。我们的研究提供了一个框架，用于理解 GSDMD 的自动抑制、脂质结合和寡聚化，这是通过重叠的界面实现的。
