La protein is a potent regulator of replication of hepatitis C virus in patients with chronic hepatitis C through internal ribosomal entry site-directed translation
La protein is a potent regulator of replication of hepatitis C virus in patients with chronic hepatitis C through internal ribosomal entry site-directed translation
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DOI：
10.1053/j.gastro.2004.11.064
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发表时间：
2005-02-01
期刊：
影响因子：
29.4
通讯作者：
Kaneko, S
中科院分区：
文献类型：
--
作者：
Honda, M;Shimazaki, T;Kaneko, S
背景与目的：丙型肝炎病毒的翻译是病毒复制的重要步骤，由内部核糖体进入位点介导。我们以前报道过丙型肝炎病毒内部核糖体进入位点在合成期（S）或有丝分裂期（M）最活跃，在静止期（GO）最低。在这里，我们调查了负责丙型肝炎病毒内部核糖体进入位点的调节的宿主因素。研究方法：我们同步的细胞周期进程，并评估宿主因子的基因表达动力学和丙型肝炎病毒内部核糖体进入位点活性的动力学在细胞周期的各个点，通过使用互补的DNA微阵列。我们还验证了确定的宿主因素对丙型肝炎病毒在体内复制的意义。结果：丙型肝炎病毒内部核糖体进入位点活性与S期和G（2）/M期诱导的基因簇相关。值得注意的是，大多数已知与丙型肝炎病毒内部核糖体进入位点结合或相互作用的起始因子[多聚（rC）结合蛋白2、多聚嘧啶束结合蛋白、真核起始因子3、真核起始因子2 γ、真核起始因子20、La蛋白和异源核核糖核蛋白L]在S期和G2/M期被诱导。La蛋白、多聚嘧啶序列结合蛋白和真核起始因子3（p116，p170）的表达主要在Go期被抑制，而在S期和G（2）/M期被诱导。在RCF-26中抑制或过表达La蛋白和多聚嘧啶道结合蛋白可显著改变丙型肝炎病毒内部核糖体进入位点活性。在慢性丙型肝炎患者的肝脏中，La蛋白的表达显著增加，并与丙型肝炎病毒RNA的量相关。结论：丙型肝炎病毒利用宿主因子在细胞分裂过程中诱导，而不是在静止期复制。其中，La蛋白是一种有效的调节剂，可增强慢性丙型肝炎患者再生肝细胞中丙型肝炎病毒的复制。
Background & Aims: Translation of hepatitis C virus is an essential step of viral replication and is mediated by an internal ribosome entry site. We previously reported that the hepatitis C virus internal ribosome entry site is most active during the synthetic (S) or mitotic (M) phases and lowest during quiescent (GO) phase. Here, we investigated host factors responsible for the regulation of the hepatitis C virus internal ribosome entry site. Methods: We synchronized the cell-cycle progression and evaluated gene-expression dynamics of host factors and kinetics of hepatitis C virus internal ribosome entry site activity in cells at various points during the cell cycle by using a complementary DNA microarray. We also validated the significance of identified host factors on hepatitis C virus replication in vivo. Results: Hepatitis C virus internal ribosome entry site activity correlated with a gene cluster induced in the S and G(2)/M phases. It is interesting to note that most initiation factors known to bind or interact with the hepatitis C virus internal ribosome entry site [poly(rC)-binding protein 2, polypyrimidine tract binding protein, eukaryotic initiation factor 3, eukaryotic initiation factor 2gamma, eukaryotic initiation factor 20, La protein, and heterogenous nuclear ribonucleoprotein L] were induced during the S and G2/M phases. Expression of La protein, polypyrimidine tract binding protein, and eukaryotic initiation factor 3 (p116, p170) were predominantly repressed in Go phase and induced in S and G(2)/M phases. Suppression or overexpression of La protein and polypyrimidine tract binding protein in RCF-26 significantly changed hepatitis C virus internal ribosome entry site activity. In the livers of patients with chronic hepatitis C, expression of La protein was significantly increased and correlated with the amount of hepatitis C virus RNA. Conclusions: Hepatitis C virus uses host factors induced during cell division but not during quiescence for replication. Of these, La protein is a potent regulator and enhances hepatitis C virus replication in regenerating hepatocytes in patients with chronic hepatitis C.