Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity-Dependent Attenuation of the IFN-Related Pathway
Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity-Dependent Attenuation of the IFN-Related Pathway
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Set7 通过 IFN 相关途径的酶活性依赖性减弱促进丙型肝炎病毒复制
DOI：
10.4049/jimmunol.1400583
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发表时间：
2015-03-15
影响因子：
4.4
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
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作者：
Han, Tao;Wan, Yushun;Zhu, Ying
丙型肝炎病毒感染是慢性肝病的主要原因，通常通过逃避宿主的免疫反应而导致持续感染，包括肝脏脂肪变性、肝硬变和肝细胞癌。Set7是一种赖氨酸特异性甲基转移酶，参与基因调控和病毒复制。然而，丙型肝炎病毒和Set7之间免疫逃避的机制还不是很清楚。在这项研究中，我们观察到在Huh7.5.1细胞中Set7的表达被丙型肝炎病毒感染上调，并且在丙型肝炎患者的血清、PBMCs和肝组织中也发现了相对于健康人的高水平的Set7表达。进一步的研究表明，Set7以一种酶活性依赖的方式增强了丙型肝炎病毒的复制。此外，我们的数据显示，Set7降低了病毒诱导的干扰素及其相关效应因子的表达，如dsRNA激活的蛋白激酶和29，59-寡腺苷合成酶。进一步的研究表明，Set7通过减少干扰素调节因子3/7和核因子-kappaB的p65亚基的核转位来抑制内源性干扰素的表达，并通过抑制STAT1和STAT2的磷酸化来降低干扰素诱导的dsRNA激活的蛋白激酶和29，59-寡腺苷合成酶的表达。此外，位于JAK/STAT通路上游的干扰素受体，包括IFNAR1和IFNAR2，被Set7减少。综上所述，我们的结果表明，Set7通过减弱干扰素信号通路和干扰素相关效应来促进丙型肝炎病毒的复制。
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host's immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5.1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity-dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 29,59-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-kappa B and reduced IFN-induced dsRNA-activated protein kinase and 29,59-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors.