Caspase-1 initiates apoptosis in the absence of gasdermin D
Caspase-1 initiates apoptosis in the absence of gasdermin D
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DOI：
10.1038/s41467-019-09753-2
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发表时间：
2019-05-07
影响因子：
16.6
通讯作者：
Suda, Takashi
中科院分区：
文献类型：
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作者：
Tsuchiya, Kohsuke;Nakajima, Shinsuke;Suda, Takashi
在炎性小体中激活的Caspase-1触发一种被称为焦亡的程序性坏死，这是由气皮蛋白D （GSDMD）介导的。然而，gsdmd缺陷细胞仍然容易发生caspase-1介导的细胞死亡。因此，在这里，我们研究了caspase-1在gsdmd缺陷细胞中引发细胞死亡的机制。炎性小体刺激诱导gsdmd缺陷巨噬细胞凋亡并伴有caspase-3激活，这在很大程度上依赖于caspase-1。caspase-1的化学二聚化在gsdmd充足的细胞中诱导凋亡，而在gsdmd缺乏的细胞中诱导凋亡。caspase- 1诱导的凋亡涉及Bid-caspase-9-caspase-3轴，随后可能发生gsdme依赖性继发性坏死/焦亡。然而，Bid消融并不能完全消除细胞死亡，提示存在另一种机制。此外，皮质神经元和肥大细胞在缺氧葡萄糖剥夺和尼日利亚霉素刺激后，GSDMD表达很少或较低，并分别以caspase-1和bid依赖的方式发生凋亡。本研究阐明了caspase-1在gsdmd低/零细胞类型中诱导凋亡的分子机制和生物学作用。
Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDMEdependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.