Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.
Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.
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NOD2受体和胞质蛋白激酶RIPK2在细菌感染过程中调节NF-κB和MAP激酶信号，但这一免疫轴在病毒感染过程中的作用尚未得到解决。我们证明Nod2−/−和Ripk2−/−小鼠对甲型流感病毒感染易感。Ripk2−/−细胞表现出线粒体自噬缺陷，导致线粒体超氧化物产生增强，受损线粒体积累，导致NLRP3炎性体激活和IL-18产生增加。RIPK2通过磷酸化线粒体自噬诱导剂ULK1，以激酶依赖的方式调节线粒体自噬。因此，Ulk1−/−细胞显示出增强的线粒体超氧化物产生和caspase-1激活。这些结果表明，NOD2-RIPK2信号通过负性调节NLRP3炎性体的激活和IL-18的产生，通过ulk1依赖性的有丝分裂，对病毒引发的免疫病理起到保护作用。
NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2−/− and Ripk2−/− mice are hypersusceptible to influenza A virus infection. Ripk2−/− cells displayed defective mitophagy leading to enhanced mitochondrial superoxide production and accumulation of damaged mitochondria resulting in increased NLRP3 inflammasome activation and IL-18 production. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1−/− cells displayed enhanced mitochondrial superoxide production and caspase-1 activation. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating NLRP3 inflammasome activation and IL-18 production via ULK1-dependent mitophagy.
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