Please use this identifier to cite or link to this item: http://cmuir.cmu.ac.th/jspui/handle/6653943832/51262
Title: Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling
Authors: Kattareeya Kumthip
Pattranuch Chusri
Nikolaus Jilg
Lei Zhao
Dahlene N. Fusco
Hong Zhao
Kaku Goto
Du Cheng
Esperance A. Schaefer
Leiliang Zhang
Chansom Pantip
Satawat Thongsawat
Amornrat O'Brien
Lee F. Peng
Niwat Maneekarn
Raymond T. Chung
Wenyu Lin
Keywords: Agricultural and Biological Sciences
Immunology and Microbiology
Issue Date: 1-Aug-2012
Abstract: Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5A's contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment. © 2012, American Society for Microbiology.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84865086668&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/51262
ISSN: 10985514
0022538X
Appears in Collections:CMUL: Journal Articles

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