Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitin-independent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G1/S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ-mediated p16 degradation in HBV tumorigenesis.

中文翻译：

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乙型肝炎病毒X蛋白通过PA28γ介导的蛋白酶体降解下调p16水平来刺激细胞生长。

蛋白酶体激活剂28γ（PA28γ）是20S蛋白酶体的必需成分，负责靶蛋白的遍在蛋白非依赖性降解，通常在肝细胞癌中过表达。最近，我们报道了乙型肝炎病毒（HBV）X蛋白（HBx）通过上调p53水平激活人类肝细胞中PA28γ的表达。然而，其在HBV肿瘤发生中的作用仍然未知。在这里，我们发现了HBx -激活PA28γ下调通过泛素-蛋白酶体无关降解P16的水平。结果，HBx激活了Rb-E2F途径并刺激了G 1 / S细胞周期进程，导致细胞增殖增加。在1.2聚体HBV复制子中和在体外复制了HBx诱导这些作用的潜力HBV感染系统几乎完全被要么PA28γ敲除或过表达P16取消，充分展示了PA28γ的关键作用-乙肝病毒介导的肿瘤退化P16。