Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Eur J Immunol. 2018 Apr;48(4):584-592. doi: 10.1002/eji.201747404. Epub 2018 Jan 15.
The pro-inflammatory cytokine IL-1β is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro-form by the inflammatory caspase-1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin-D has been identified as a new target of caspase-1. After proteolytical cleavage of gasdermin-D, the N-terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin-D is required for IL-1β secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell-lysis-independent event. Liposome transport assays in vitro further demonstrate that gasdermin-D pores are large enough to allow the direct release of IL-1β. Moreover, IL-18 and other small soluble cytosolic proteins can also be released in a lysis-independent but gasdermin-D-dependent mode, suggesting that the gasdermin-D pores allow passive the release of cytosolic proteins in a size-dependent manner.
促炎细胞因子白细胞介素-1β (IL-1β) 以其在宿主防御和引发强烈炎症反应中的作用而闻名。它由炎症性半胱天冬酶-1（caspase-1）将其无活性的前体形式加工成成熟的生物活性形式，然后通过非经典分泌机制从细胞中释放出来。最近，gasdermin-D 已被确定为 caspase-1 的一个新靶点。gasdermin-D 经蛋白水解切割后，其 N 端片段通过在质膜上形成大的通透性孔，诱导细胞发生焦亡，即一种裂解性细胞死亡。在这里，我们使用小鼠系统表明，gasdermin-D 是巨噬细胞、树突状细胞和部分中性粒细胞中 IL-1β 分泌所必需的，并且分泌是一种与细胞裂解无关的事件。体外脂质体转运实验进一步表明，gasdermin-D 孔足够大，可以允许 IL-1β 的直接释放。此外，IL-18 和其他小的可溶性胞质蛋白也可以以不依赖裂解但依赖 gasdermin-D 的方式释放，这表明 gasdermin-D 孔允许以大小依赖的方式被动释放胞质蛋白。
