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Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10443-8. doi: 10.1073/pnas.1513341112. Epub 2015 Jul 27.

Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness.

Author information

1
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
2
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
3
Department of Pathology, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea;
4
Department of Surgery, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea;
5
Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
6
Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-040, Republic of Korea.
7
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; ecshin@kaist.ac.kr starkg@ccf.org.
8
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea; ecshin@kaist.ac.kr starkg@ccf.org.

Abstract

Up-regulation of IFN-stimulated genes (ISGs) is sustained in hepatitis C virus (HCV)-infected livers. Here, 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. The level of U-ISGF3, but not tyrosine phosphorylated STAT1, is significantly elevated in response to IFN-λ and IFN-β during chronic HCV infection. U-ISGF3 prolongs the expression of a subset of ISGs and restricts HCV chronic replication. However, paradoxically, high levels of U-ISGF3 also confer unresponsiveness to IFN-α therapy. As a mechanism of U-ISGF3-induced resistance to IFN-α, we found that ISG15, a U-ISGF3-induced protein, sustains the abundance of ubiquitin-specific protease 18 (USP18), a negative regulator of IFN signaling. Our data 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.

KEYWORDS:

U-ISGF3; hepatitis C virus; interferon; interferon-stimulated genes

PMID:
26216956
PMCID:
PMC4547285
DOI:
10.1073/pnas.1513341112
[Indexed for MEDLINE]
Free PMC Article

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