Vaccine and Infectious Disease Organization-International Vaccine Center and Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Vaccine and Infectious Disease Organization-International Vaccine Center and School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Sci Rep. 2017 Jun 16;7(1):3695. doi: 10.1038/s41598-017-03052-w.
Hepatitis C virus (HCV) infection leads to severe liver diseases including hepatocellular carcinoma (HCC). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumour suppressor, is frequently mutated or deleted in HCC tumors. PTEN has previously been demonstrated to inhibit HCV secretion. In this study, we determined the effects of PTEN on the other steps in HCV life cycle, including entry, translation, and replication. We showed that PTEN inhibits HCV entry through its lipid phosphatase activity. PTEN has no effect on HCV RNA translation. PTEN decreases HCV replication and the protein phosphatase activity of PTEN is essential for this function. PTEN interacts with the HCV core protein and requires R50 in domain I of HCV core and PTEN residues 1-185 for this interaction. This interaction is required for PTEN-mediated inhibition of HCV replication. This gives rise to a reduction in PTEN levels and intracellular lipid abundance, which may in turn regulate HCV replication. HCV core domain I protein increases the lipid phosphatase activity of PTEN in an in vitro assay, suggesting that HCV infection can also regulate PTEN. Taken together, our results demonstrated an important regulatory role of PTEN in the HCV life cycle.
丙型肝炎病毒（HCV）感染可导致严重的肝脏疾病，包括肝细胞癌（HCC）。磷酸酶和张力蛋白同源物缺失于染色体 10 号（PTEN）是一种肿瘤抑制因子，在 HCC 肿瘤中经常发生突变或缺失。PTEN 先前已被证明可抑制 HCV 的分泌。在这项研究中，我们确定了 PTEN 对 HCV 生命周期中其他步骤的影响，包括进入、翻译和复制。我们表明，PTEN 通过其脂质磷酸酶活性抑制 HCV 进入。PTEN 对 HCV RNA 翻译没有影响。PTEN 降低 HCV 复制，PTEN 的蛋白磷酸酶活性对该功能至关重要。PTEN 与 HCV 核心蛋白相互作用，需要 HCV 核心的域 I 中的 R50 和 HCV 核心的残基 1-185 以及 PTEN 来进行相互作用。这种相互作用是 PTEN 介导的 HCV 复制抑制所必需的。这导致 PTEN 水平和细胞内脂质丰度降低，这可能反过来调节 HCV 复制。HCV 核心结构域 I 蛋白在体外测定中增加了 PTEN 的脂质磷酸酶活性，表明 HCV 感染也可以调节 PTEN。总之，我们的结果表明 PTEN 在 HCV 生命周期中具有重要的调节作用。
