The regulated disruption of the plasma membrane, which can promote cell death, cytokine secretion or both is central to organismal health. The protein gasdermin D (GSDMD) is a key player in this process. GSDMD forms membrane pores that can promote cytolysis and the release of interleukin-1 family cytokines into the extracellular space. Recent discoveries have revealed biochemical and cell biological mechanisms that control GSDMD pore-forming activity and its diverse downstream immunological effects. Here, we review these multifaceted regulatory activities, including mechanisms of GSDMD activation by proteolytic cleavage, dynamics of pore assembly, regulation of GSDMD activities by posttranslational modifications, membrane repair and the interplay of GSDMD and mitochondria. We also address recent insights into the evolution of the gasdermin family and their activities in species across the kingdoms of life. In doing so, we hope to condense recent progress and inform future studies in this rapidly moving field in immunology.

质膜的受调节破坏可以促进细胞死亡、细胞因子分泌或两者兼而有之，这对于机体健康至关重要。蛋白质gasdermin D (GSDMD) 是这一过程中的关键角色。GSDMD 形成膜孔，可以促进细胞溶解以及将 IL-1 家族细胞因子释放到细胞外空间。最近的发现揭示了控制 GSDMD 成孔活性及其多种下游免疫效应的生化和细胞生物学机制。在这里，我们回顾了这些多方面的调节活动，包括通过蛋白水解裂解激活 GSDMD 的机制、孔组装的动力学、通过翻译后修饰调节 GSDMD 活性、膜修复以及 GSDMD 和线粒体的相互作用。我们还阐述了对 Gasdermin 家族的进化及其在生命王国各个物种中的活动的最新见解。在此过程中，我们希望凝聚最新进展，并为免疫学这一快速发展领域的未来研究提供信息。