STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease
STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease
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DOI：
10.1073/pnas.1308331110
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发表时间：
2013-10-08
影响因子：
11.1
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
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作者：
Petrasek, Jan;Iracheta-Vellve, Arvin;Szabo, Gyongyi
新出现的证据表明，固有免疫驱动酒精性肝病（ALD），并且干扰素调节因子3（IRF3）——一种调节固有免疫反应的转录因子，对于ALD的发展是不可或缺的。在此我们报道，IRF3通过将内质网（ER）应激与肝细胞中的凋亡信号传导联系起来介导ALD。我们发现乙醇诱导内质网应激，并触发IRF3与内质网接头蛋白、干扰素基因刺激因子（STING）结合，以及随后IRF3的磷酸化。活化的IRF3与促凋亡分子Bax[B细胞淋巴瘤2（Bcl2）相关X蛋白]结合，并促进肝细胞凋亡。STING缺失可阻止乙醇或内质网应激诱导的IRF3磷酸化，而IRF3缺失可阻止肝细胞凋亡。IRF3在ALD中的致病作用不依赖于炎症或I型干扰素。因此，STING和IRF3是ALD的关键决定因素，它们将内质网应激信号传导与肝细胞凋亡的线粒体途径联系起来。
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3), a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis.