Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.
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.
Foy
Eileen
E
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9048, USA.
Li
Kui
K
Wang
Chunfu
C
Sumpter
Rhea
R
Ikeda
Masanori
M
Lemon
Stanley M
SM
Gale
Michael
M
D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D006526:Hepatitis C / Q000628:therapy / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D012367:RNA, Viral / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014779:Virus Replication; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D011480:Protease Inhibitors; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D012697:Serine Endopeptidases; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases