Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Science. 2018 Nov 30;362(6418):1064-1069. doi: 10.1126/science.aau2818. Epub 2018 Oct 25.
Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome-dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.
gasdermin D（GSDMD）的有限蛋白水解生成控制巨噬细胞细胞焦亡的 N 端孔形成片段。GSDMD 通过炎性体激活的半胱天冬酶-1 或 -11 进行加工。目前尚不清楚巨噬细胞 GSDMD 是否可以通过其他机制进行加工。在这里，我们描述了控制 GSDMD 加工的另一种途径。效应蛋白 YopJ 抑制 TAK1 或 IκB 激酶（IKK）可引发 RIPK1 和半胱天冬酶-8 依赖性 GSDMD 切割，随后导致细胞死亡。GSDMD 加工也有助于 NLRP3 炎性体依赖性白细胞介素-1β（IL-1β）的释放。因此，半胱天冬酶-8 作为 GSDMD 驱动的细胞死亡的调节剂。此外，本研究确立了 TAK1 和 IKK 活性在控制 GSDMD 切割和细胞毒性中的重要性。
