Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness
Up-regulation of IFN-stimulated genes (ISGs) is sustained in hepatitis C virus (HCV)-infected livers. In the present study, we investigated the mechanism of prolonged ISG expression and its role in IFN responsiveness during HCV infection in relation to unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), recently identified as a tripartite transcription factor formed by high levels of IFN response factor 9 (IRF9), STAT1, and STAT2 without tyrosine phosphorylation of the STATs. We demonstrate that U-ISGF3 induced by IFN-λs and -β drives prolonged expression of a set of ISGs, leading to chronic activation of innate responses and conferring a lack of response to IFN-α in HCV-infected liver.
Hepatitis C virus (HCV) infection stimulates the production of endogenous interferons (IFNs) and the following persistent activation of interferon-stimulated genes (ISGs) in the infected liver. In the patients with chronic HCV infection, high levels of activated ISGs in the liver at baseline were proved to predict poor response to pegylated IFN-α/ribavirin therapy. In this report, we demonstrate that the level of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), not ISGF3, is increased by endogenous IFN-λs and IFN-β in HCV-infected hepatocytes and livers, leading to persistent activation of a set of ISGs. We also demonstrate that the high level of ISG15 induced by U-ISGF3 resulted in an increased level of ubiquitin-specific protease 18 (USP18), a critical negative regulator of the response to exogenous IFN-α.
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Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10443-8. doi: 10.1073/pnas.1513341112.
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