Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea.
J Gen Virol. 2020 Sep;101(9):963-971. doi: 10.1099/jgv.0.001461.
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 HBxactivated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G/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 HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γmediated p16 degradation in HBV tumorigenesis.
蛋白酶体激活因子 28 γ（PA28γ）是 20S 蛋白酶体的必需组成部分，负责泛素非依赖性靶蛋白的降解，在肝细胞癌中经常过表达。最近，我们报道乙型肝炎病毒（HBV）X 蛋白（HBx）通过上调 p53 水平激活人肝细胞中的 PA28γ表达；然而，其在 HBV 致癌作用中的作用尚不清楚。在这里，我们发现 HBx 激活的 PA28γ 通过非泛素依赖性蛋白酶体降解下调 p16 水平。结果，HBx 激活了 Rb-E2F 通路并刺激了 G1/S 细胞周期进程，导致细胞增殖增加。1.2mer HBV 复制子和 HBV 感染系统中可以再现 HBx 诱导这些效应的能力，并且通过 PA28γ 敲低或 p16 过表达几乎完全消除了这些能力，表明 PA28γ 介导的 p16 降解在 HBV 致癌作用中起着关键作用。
