The mechanisms underlying the release of interleukin-1 (IL-1) family cytokines from phagocytes have been the subject of intense investigations for more than 30 years. The absence of an amino-terminal secretion signal from members of this family suggests a previously unknown mechanism of protein secretion that transfers cytosolic IL-1 directly across the plasma membrane into the extracellular space. The pore-forming protein gasdermin D (GSDMD) has emerged as the conduit for IL-1 secretion from the cytosol, serving to induce the release of IL-1 from living (hyperactive) or dead (pyroptotic) cells. In this Review, we discuss the mechanism by which GSDMD pore formation is regulated by the activity of inflammatory caspases, which are commonly associated with inflammasomes. We discuss how GSDMD promotes IL-1 release from hyperactive or pyroptotic cells, with a specific focus on defining how these distinct cell fates associated with GSDMD activity can be regulated. Last, the physiological consequences of GSDMD activity and therapeutic potential of targeting this pore-forming protein are discussed, which highlight the abundance of questions that remain to be answered by the community.

中文翻译：

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Gasdermin D在炎症和宿主防御中具有活性。

30多年来，吞噬细胞释放白介素1（IL-1）家族细胞因子的潜在机制一直是深入研究的主题。来自该家族成员的氨基末端分泌信号的缺乏表明蛋白质分泌的先前未知的机制，其将胞浆IL-1直接穿过质膜转移到细胞外空间。形成孔的蛋白gasdermin D（GSDMD）已作为从细胞质中分泌IL-1的管道，用于诱导IL-1从活细胞（多动的）或死细胞（化脓的）的释放。在这篇综述中，我们讨论了GSDMD孔形成受炎症性胱天蛋白酶（通常与炎症小体相关）调节的机制。我们讨论了GSDMD如何促进过度活跃或烧焦细胞中IL-1的释放，特别着重于定义如何调节与GSDMD活性相关的这些独特的细胞命运。最后，讨论了GSDMD活性的生理后果以及靶向这种成孔蛋白的治疗潜力，这些都凸显了社区仍需回答的大量问题。