Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
Sci Adv. 2020 Nov 18;6(47). doi: 10.1126/sciadv.abc3465. Print 2020 Nov.
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 infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti- 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.
Gasdermin D（GSDMD）是一种形成孔的蛋白，可促进细胞焦亡和促炎细胞因子的释放。最近的研究表明，凋亡 Caspase-8 可直接切割 GSDMD 以触发细胞焦亡。然而，Caspase-8 依赖性 GSDMD 切割的分子要求以及该信号轴的生理影响仍未解决。在这里，我们报告 Caspase-8 依赖性 GSDMD 切割赋予了对肿瘤坏死因子（TNF）诱导的致死性的易感性，而与 Caspase-1 无关，并且 GSDMD 的激活为宿主提供了对抗感染的防御能力。我们进一步证明，凋亡 Caspase 在天冬氨酸 88（D88）处对 GSDMD 的失活可抑制 TNF 诱导的致死性，但可促进抗防御作用。最后，我们表明 Caspase-8 二聚化和自身加工是 GSDMD 切割所必需的，并提供了证据表明，Caspase-8 自身加工和对各种复合物的活性与其直接切割 GSDMD 的能力相关。这些发现揭示了 GSDMD 作为一种潜在的治疗靶标，可减少与死亡受体信号机制中的突变相关的炎症。
