Staufen1 promotes HCV replication by inhibiting protein kinase R and transporting viral RNA to the site of translation and replication in the cells.
Staufen1 promotes HCV replication by inhibiting protein kinase R and transporting viral RNA to the site of translation and replication in the cells.
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DOI：
10.1093/nar/gkw312
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发表时间：
2016-06-20
影响因子：
14.9
通讯作者：
Pandey VN
中科院分区：
文献类型：
--
作者：
Dixit U;Pandey AK;Mishra P;Sengupta A;Pandey VN
持续性丙型肝炎病毒（HCV）感染导致慢性丙型肝炎（CHC），其通常进展为肝硬化（LC）和肝细胞癌（HCC）。建立CHC并导致其随后发展为LC和HCC的分子机制知之甚少。我们已经确定了一个细胞质双链RNA结合蛋白，Stau 1，这是至关重要的HCV复制。Stau 1与HCV 3′端NTR的可变茎环区和5′端NTR的HCV-IRES结构域IIId特异性相互作用，促进HCV的复制和翻译。Stau 1共免疫沉淀HCV NS 5 B和细胞因子蛋白激酶R（PKR），这对干扰素诱导的细胞抗病毒和抗增殖反应至关重要。与Stau 1一样，PKR对HCV-IRES的结构域IIId具有结合特异性。Stau 1与PKR结合并强烈抑制PKR-自磷酸化。我们证明了HCV RNA在多核糖体上的转运是依赖于Stau 1的，当Stau 1下调时主要定位在单核糖体组分中，而当Stau 1过表达时仅定位在多核糖体中。我们的研究结果表明，HCV可能适当的Stau 1，以防止PKR介导的抑制eIF 2 α，这是必要的HCV蛋白质的合成，病毒RNA基因组易位到多核糖体的有效翻译和复制。
Persistent hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms that establish CHC and cause its subsequent development into LC and HCC are poorly understood. We have identified a cytoplasmic double-stranded RNA binding protein, Stau1, which is crucial for HCV replication. In this study, Stau1 specifically interacted with the variable-stem-loop region in the 3′ NTR and domain IIId of the HCV-IRES in the 5′ NTR, and promoted HCV replication and translation. Stau1 coimmunoprecipitates HCV NS5B and a cell factor, protein kinase R (PKR), which is critical for interferon-induced cellular antiviral and antiproliferative responses. Like Stau1, PKR displayed binding specificity to domain IIId of HCV-IRES. Stau1 binds to PKR and strongly inhibits PKR-autophosphorylation. We demonstrated that the transport of HCV RNA on the polysomes is Stau1-dependent, being mainly localized in the monosome fractions when Stau1 is downregulated and exclusively localized in the polysomes when Stau1 is overexpressed. Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR-mediated inhibition of eIF2α, which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication.