title: Set7 facilitates hepatitis C virus replication via enzymatic activity-dependent attenuation of the IFN-related pathway.
abstract: 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 2',5'-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-κB and reduced IFN-induced dsRNA-activated protein kinase and 2',5'-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.
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Tao
authors: T
authors: Han
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Yushun
authors: Y
authors: Wan
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Jun
authors: J
authors: Wang
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Peng
authors: P
authors: Zhao
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Yue
authors: Y
authors: Yuan
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Li
authors: L
authors: Wang
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Yinglong
authors: Y
authors: She
authors: Medical Faculty, Department of Gastroenterology and Hepatology, University of Duisburg-Essen, 45127 Essen, Germany; and.
authors: Ruth
authors: R
authors: Broering
authors: Institute of Virology, University of Duisburg-Essen, 45127 Essen, Germany.
authors: Mengji
authors: M
authors: Lu
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;
authors: Linbai
authors: L
authors: Ye
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; yingzhu@whu.edu.cn.
authors: Ying
authors: Y
authors: Zhu
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006521:Hepatitis, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human