Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease
Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease
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DOI：
10.1126/science.1082604
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发表时间：
2003-05-16
期刊：
影响因子：
56.9
通讯作者：
Gale, M
中科院分区：
文献类型：
--
作者：
Foy, E;Li, K;Gale, M
丙型肝炎病毒（HCV）的持续感染可能依赖于病毒对宿主防御的抑制。我们发现HCV NS 3/4A丝氨酸蛋白酶阻断了干扰素调节因子-3（IRF-3）的磷酸化和效应作用，IRF-3是一种关键的细胞抗病毒信号分子。通过突变或酮酰胺拟肽抑制剂破坏NS 3/4A蛋白酶功能，缓解了这种阻断，并在用不相关病毒进行细胞攻击后恢复了IRF-3磷酸化。此外，显性阴性或组成型活性IRF-3突变体，分别增强或抑制肝癌细胞中的HCV RNA复制。因此，NS 3/4A蛋白酶代表双重治疗靶标，其抑制可以阻断病毒复制并恢复HCV感染的IRF-3控制。
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.