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Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.
| Title | Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. |
| Publication Type | Journal Article |
| Year of Publication | 2003 |
| Authors | Foy, E, Li, K, Wang, C, Sumpter, R, Ikeda, M, Lemon, SM, Gale, M |
| Journal | Science |
| Volume | 300 |
| Issue | 5622 |
| Pagination | 1145-8 |
| Date Published | 2003 May 16 |
| ISSN | 1095-9203 |
| Keywords | DNA-Binding Proteins, Gene Expression Regulation, Gene Expression Regulation, Viral, Hepacivirus, Hepatitis C, Humans, Interferon Regulatory Factor-3, Interferons, Mutation, Phosphorylation, Protease Inhibitors, RNA, Viral, RNA-Binding Proteins, Serine Endopeptidases, Transcription Factors, Tumor Cells, Cultured, Viral Nonstructural Proteins, Virus Replication |
| Abstract | Persistent infections with hepatitis C virus (HCV) are likely to depend on viral inhibition of host defenses. We show that the HCV NS3/4A serine protease blocks the phosphorylation and effector action of interferon regulatory factor-3 (IRF-3), a key cellular antiviral signaling molecule. Disruption of NS3/4A protease function by mutation or a ketoamide peptidomimetic inhibitor relieved this blockade and restored IRF-3 phosphorylation after cellular challenge with an unrelated virus. Furthermore, dominant-negative or constitutively active IRF-3 mutants, respectively, enhanced or suppressed HCV RNA replication in hepatoma cells. Thus, the NS3/4A protease represents a dual therapeutic target, the inhibition of which may both block viral replication and restore IRF-3 control of HCV infection. |
| DOI | 10.1126/science.1082604 |
| Alternate Journal | Science |
| PubMed ID | 12702807 |
