Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.
Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.
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DOI：
10.1126/sciadv.abc3465
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发表时间：
2020-11
期刊：
影响因子：
13.6
通讯作者：
Broz P
中科院分区：
文献类型：
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作者：
Demarco B;Grayczyk JP;Bjanes E;Le Roy D;Tonnus W;Assenmacher CA;Radaelli E;Fettrelet T;Mack V;Linkermann A;Roger T;Brodsky IE;Chen KW;Broz P
Caspase-8依赖性GSDMD激活促进抗菌防御;然而，该途径也可介导体内TNF休克。Gasdermin D（GSDMD）是一种促进焦亡和促炎细胞因子释放的成孔蛋白。最近的研究表明，凋亡的caspase-8直接切割GSDMD，引发细胞凋亡。然而，半胱天冬酶-8依赖性GSDMD切割的分子要求和该信号传导轴的生理影响尚未得到解决。在这里，我们报告说，caspase-8依赖GSDMD裂解赋予肿瘤坏死因子（TNF）诱导的致死独立的caspase-1和GSDMD激活提供宿主防御耶尔森氏菌感染的易感性。我们进一步证明，GSDMD的天冬氨酸88（D88）的凋亡半胱天冬酶失活抑制TNF诱导的致死性，但促进抗耶尔森氏菌防御。最后，我们表明，胱天蛋白酶-8二聚化和自动加工所需的GSDMD切割，并提供证据表明，胱天蛋白酶-8自动加工和各种复合物的活性与其直接切割GSDMD的能力。这些发现揭示了GSDMD作为一个潜在的治疗靶点，以减少与死亡受体信号机制突变相关的炎症。
Caspase-8–dependent GSDMD activation promotes antibacterial defense; however, this pathway can also mediate TNF shock in vivo. Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8–dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved. Here, we report that caspase-8–dependent GSDMD cleavage confers susceptibility to tumor necrosis factor (TNF)–induced lethality independently of caspase-1 and that GSDMD activation provides host defense against Yersinia infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti-Yersinia defense. Last, we show that caspase-8 dimerization and autoprocessing are required for GSDMD cleavage, and provide evidence that the caspase-8 autoprocessing and activity on various complexes correlate with its ability to directly cleave GSDMD. These findings reveal GSDMD as a potential therapeutic target to reduce inflammation associated with mutations in the death receptor signaling machinery.