Laboratory of Genetics and Physiology 2 (LGP2) Plays an Essential Role in Hepatitis C Virus Infection-Induced Interferon Responses
Laboratory of Genetics and Physiology 2 (LGP2) Plays an Essential Role in Hepatitis C Virus Infection-Induced Interferon Responses
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DOI：
10.1002/hep.29050
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发表时间：
2017-05-01
期刊：
影响因子：
13.5
通讯作者：
Zhong, Jin
中科院分区：
文献类型：
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作者：
Hei, Lei;Zhong, Jin
视黄酸诱导基因I（RIG-I）样受体是检测非自身RNA并激活下游干扰素（IFN）信号传导的胞质模式识别受体（PRR）。RIG-I样受体之一，遗传学和生理学实验室2（LGP 2），最初被认为是RIG-I信号通路中的负反馈调节剂，但越来越多的证据表明LGP 2是黑素瘤分化相关蛋白5（MDA 5）介导的IFN信号激活中的一个辅因子。我们的前期工作表明，MDA 5是检测丙型肝炎病毒（HCV）感染肝细胞的主要PRR，但LGP 2在HCV感染诱导的IFN信号转导中的作用尚未阐明。在这项研究中，我们报道了LGP 2是HCV感染诱导的IFN信号转导的正调控因子。敲除肝细胞中的LGP 2显著减少了对HCV感染的IFN产生，但对HCV 3'非翻译区RNA转染没有影响。机制研究表明，LGP 2在IFN信号转导中MDA 5上游一步发挥作用。HCV感染促进了LGP 2与MDA 5之间的分子相互作用，从而增强了MDA 5/HCV RNA的结合。最后，我们证明了LGP 2的ATP酶活性在HCV感染过程中对协助MDA 5/HCV RNA相互作用和激活IFN信号传导至关重要。结论：我们的工作表明，LGP 2通过促进HCV病原体相关分子模式的MDA 5识别，在激活IFN信号转导对抗HCV感染中起重要作用。
Retinoic acid-inducible gene I (RIG-I)-like receptors are cytosolic pattern recognition receptors (PRRs) that detect non-self-RNA and activate downstream interferon (IFN) signaling. One of the RIG-I-like receptors, laboratory of genetics and physiology 2 (LGP2), was originally thought to be a negative feedback regulator in the RIG-I signaling pathway, but growing evidence indicates that LGP2 is one cofactor of melanoma differentiation-associated protein 5 (MDA5) in MDA5-mediated IFN signaling activation. Our previous work showed that MDA5 was the major PRR to sense hepatitis C virus (HCV) infection in hepatocytes, but the role of LGP2 in HCV infection-induced IFN signaling has not been elucidated. In this study, we reported that LGP2 was a positive regulator of HCV infection-induced IFN signaling. Knockout of LGP2 in hepatocytes significantly diminished IFN production in response to HCV infection, but not to HCV 3' untranslated region RNA transfection. Mechanistic studies showed that LGP2 exerted its function at a step upstream of MDA5 in the IFN signaling. HCV infection promoted the molecular interaction between LGP2 and MDA5, which, in turn, enhanced MDA5/HCV RNA association. Finally, we demonstrated that the ATPase activity of LGP2 was critical for assisting MDA5/HCV RNA interaction and activating IFN signaling during HCV infection. Conclusion: Our work demonstrated that LGP2 plays an essential role in activating IFN signaling against HCV infection by promoting MDA5 recognition of HCV pathogen-associated molecular patterns.