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Proc. Natl. Acad. Sci. USA, Published online before print July 27, 2015, doi: 10.1073/pnas.1513341112
Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness
Abstract
Pil Soo Sunga, HyeonJoo Cheonb, Chung Hwan Choa, Seon-Hui Honga, Do Youn Parkc, Hyung-Il Seod, Su-Hyung Parke, Seung Kew Yoonf, George R. Starkb,1, and Eui-Cheol Shina,1
aLaboratory 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; bDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; cDepartment of Pathology, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea; dDepartment of Surgery, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea; eLaboratory 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; fDepartment of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-040, Republic of Korea
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.
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.
1To whom correspondence may be addressed.
Author contributions: P.S.S., H.C., S.K.Y., G.R.S., and E.-C.S. designed research; P.S.S., C.H.C., S.-H.H., D.Y.P., and H.-I.S. performed research; P.S.S., H.C., S.-H.P., S.K.Y., and E.-C.S. analyzed data; and P.S.S., H.C., G.R.S., and E.-C.S. wrote the paper.
논문정보
- Research article
- 2015년 07월 (BRIC 등록일 2015-08-03)
- 국내(교신)+국외 연구진
- 의약학 > 면역의학
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