期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 33, 页码 10443-10448出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1513341112
关键词
hepatitis C virus; U-ISGF3; interferon; interferon-stimulated genes
资金
- Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI13C1263]
- National Research Foundation [NRF-2012-M3C1A1-048860, NRF-2014R1A2A1A10053662]
- Korea Advanced Institute of Science and Technology Future Systems Healthcare Project
- Ministry of Science, Information/CommunicationTechnology (ICT), and Future Planning of Korea
- project of Global PhD Fellowship through the National Research Foundation of Korea - Ministry of Science, ICT, and Future Planning of Korea [NRF-2012H1A2A1012809]
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-lambda and IFN-beta 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-alpha therapy. As a mechanism of U-ISGF3-induced resistance to IFN-alpha, 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-lambda s and -beta drives prolonged expression of a set of ISGs, leading to chronic activation of innate responses and conferring a lack of response to IFN-alpha in HCV-infected liver.
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