Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.
Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.
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DOI：
10.1016/j.cell.2014.11.036
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发表时间：
2014-12-18
期刊：
影响因子：
64.5
通讯作者：
Kile BT
中科院分区：
文献类型：
--
作者：
White MJ;McArthur K;Metcalf D;Lane RM;Cambier JC;Herold MJ;van Delft MF;Bedoui S;Lessene G;Ritchie ME;Huang DC;Kile BT
活化的半胱天冬酶（caspases）是内源性凋亡途径诱导的细胞凋亡的一个标志，但在体内，它们对于细胞死亡以及细胞的凋亡清除并非不可或缺。这就引发了一种观点，即半胱天冬酶被激活不仅仅是为了杀死细胞，还为了防止濒死细胞引发宿主免疫反应。在此，我们表明半胱天冬酶级联反应可抑制正在经历Bak/Bax介导的细胞凋亡的细胞产生I型干扰素（IFN）。Bak和Bax会触发线粒体DNA的释放。这会被依赖于环鸟苷酸 - 腺苷酸合成酶（cGAS）/干扰素基因刺激蛋白（STING）的DNA感知途径识别，进而启动干扰素的产生。而活化的半胱天冬酶会减弱这种反应。药物抑制半胱天冬酶或通过基因敲除半胱天冬酶 - 9、凋亡蛋白酶激活因子 - 1（Apaf - 1），或半胱天冬酶 - 3/7，会导致濒死细胞分泌干扰素 - β。在体内，这会促使干扰素 - β水平升高，进而导致造血干细胞功能障碍，而Bak和Bax缺失则可纠正这一情况。因此，凋亡性半胱天冬酶级联反应的作用是使线粒体凋亡在免疫学上处于沉默状态。
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.