Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation
Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation
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DOI：
10.1073/pnas.2237238100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Gale, M
中科院分区：
文献类型：
--
作者：
Ye, J;Wang, CF;Gale, M
丙型肝炎病毒（HCV）RNA的复制依赖于病毒蛋白与细胞内膜的结合，但膜组成对病毒复制的影响尚不清楚。我们报告说，HCV RNA复制和装配的病毒复制复合物需要geranylgeranylation的一个或多个主机蛋白。在培养的肝癌细胞中，HCV RNA复制被破坏的治疗与洛伐他汀，3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂，或与蛋白香叶基香叶基转移酶1的抑制剂，其中每一个诱导溶解的HCV复制复合物。用法尼基转移酶抑制剂处理细胞不影响病毒复制。当加入到lovastatin处理的细胞，香叶基香叶醇，但不是法尼醇，恢复复制复合物组装和病毒复制。由于HCV基因组不编码典型的牛儿基牛儿基化蛋白，因此数据表明牛儿基牛儿基化宿主蛋白参与HCV复制。抑制其香叶基香叶基化提供了治疗HCV感染的治疗策略。
Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with lovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase 1, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to lovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV, genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.