Viral apoptosis is induced by IRF-3-mediated activation of Bax
Viral apoptosis is induced by IRF-3-mediated activation of Bax
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DOI：
10.1038/emboj.2010.50
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发表时间：
2010-05-19
期刊：
影响因子：
11.4
通讯作者：
Sen, Ganes C.
中科院分区：
文献类型：
--
作者：
Chattopadhyay, Saurabh;Marques, Joao T.;Sen, Ganes C.
在感染许多RNA病毒后，细胞质视黄酸诱导基因-I（RIG - I）通路会激活潜在的转录因子IRF - 3，导致其核转位以及许多抗病毒基因（包括编码干扰素的基因）的诱导。在此，我们报道了在病毒感染细胞中IRF - 3的一种新颖且独特的活性，即诱导细胞凋亡。利用基因缺陷的小鼠和人类细胞系，我们证明，尽管两条通路都需要RIG - I、IPS1、TRAF3和TBK1的存在，但只有凋亡通路还需要TRAF2和TRAF6的存在。更重要的是，转录失活的IRF - 3突变体，比如缺失其DNA结合域的突变体，能够有效地介导细胞凋亡。细胞凋亡是由IRF - 3通过一个新鉴定的BH3结构域与促凋亡蛋白Bax直接相互作用、它们共转位到线粒体以及由此激活线粒体凋亡通路所触发的。因此，IRF - 3是一种具有双重作用的细胞质蛋白，在激活后，它会转位到细胞核或线粒体，并触发被感染细胞的两种互补的抗病毒反应。《欧洲分子生物学组织杂志》（2010年）29卷，1762 - 1773页。doi:10.1038/emboj.2010.50；2010年4月1日在线发表
Upon infection with many RNA viruses, the cytoplasmic retinoic acid inducible gene-I (RIG-I) pathway activates the latent transcription factor IRF-3, causing its nuclear translocation and the induction of many antiviral genes, including those encoding interferons. Here, we report a novel and distinct activity of IRF-3, in virus-infected cells, that induces apoptosis. Using genetically defective mouse and human cell lines, we demonstrated that, although both pathways required the presence of RIG-I, IPS1, TRAF3 and TBK1, only the apoptotic pathway required the presence of TRAF2 and TRAF6 in addition. More importantly, transcriptionally inactive IRF-3 mutants, such as the one missing its DNA-binding domain, could efficiently mediate apoptosis. Apoptosis was triggered by the direct interaction of IRF-3, through a newly identified BH3 domain, with the pro-apoptotic protein Bax, their co-translocation to the mitochondria and the resulting activation of the mitochondrial apoptotic pathway. Thus, IRF-3 is a dual-action cytoplasmic protein that, upon activation, translocates to the nucleus or to the mitochondrion and triggers two complementary antiviral responses of the infected cell. The EMBO Journal (2010) 29, 1762-1773. doi: 10.1038/emboj.2010.50; Published online 1 April 2010