The X-linked tumor suppressor TSPX interacts and promotes degradation of the hepatitis B viral protein HBx via the proteasome pathway.
The X-linked tumor suppressor TSPX interacts and promotes degradation of the hepatitis B viral protein HBx via the proteasome pathway.
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DOI：
10.1371/journal.pone.0022979
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lau YF
中科院分区：
文献类型：
--
作者：
Kido T;Ou JH;Lau YF
乙型肝炎病毒 (HBV) 感染是肝细胞癌 (HCC) 的主要风险，也是一个严重的全球健康问题，全球有 20 亿人感染该病毒。 HBx 是病毒复制的重要因子，也是由 HBV 基因组编码的推定癌蛋白，已被证明可促进 HBV 感染的肝细胞中多个位点的致癌特性。 HBx的表达水平与HCC的发生和发展密切相关，因此调节HBx稳定性的机制对于HBV感染细胞的肿瘤发生具有重要意义。 We demonstrate that the X-linked tumor suppressor TSPX enhances the degradation of HBx through the ubiquitin-proteasome pathway. TSPX 通过其 C 端酸性尾部与 HBx 和蛋白酶体 19S 盖亚基 RPN3 相互作用。最重要的是，RPN3 的过度表达可以保护 HBx 免受蛋白酶体依赖性降解的影响，从而充当蛋白酶体依赖性降解的负调节因子。 TSPX 消除了 HBx 依赖于 RPN3 的稳定性，表明 TSPX 和 RPN3 在调节 HBx 稳定性方面具有竞争性。由于 X 定位肿瘤抑制基因的突变和/或表观遗传抑制可能显着使男性易患人类癌症，因此我们的数据表明，TSPX 诱导的 HBx 降解可能在 HBV 感染的 HCC 患者的肝癌发生中发挥关键作用。
Hepatitis B virus (HBV) infection is a major risk for hepatocellular carcinoma (HCC), and it is a serious global health problem with two billion people exposed to it worldwide. HBx, an essential factor for viral replication and a putative oncoprotein encoded by the HBV genome, has been shown to promote oncogenic properties at multiple sites in HBV-infected liver cells. The expression level of HBx closely associates with the development and progression of HCC, therefore the mechanism(s) regulating the stability of HBx is important in oncogenesis of HBV-infected cells. We demonstrate that the X-linked tumor suppressor TSPX enhances the degradation of HBx through the ubiquitin-proteasome pathway. TSPX interacts with both HBx and a proteasome 19S lid subunit RPN3 via its C-terminal acidic tail. Most importantly, over-expression of RPN3 protects HBx from, and hence acts as a negative regulator for, proteasome-dependent degradation. TSPX abrogates the RPN3-depedent stabilization of HBx, suggesting that TSPX and RPN3 act competitively in regulation of HBx stability. Since mutation and/or epigenetic repression of X-located tumor suppressor gene(s) could significantly predispose males to human cancers, our data suggest that TSPX-induced HBx degradation could play key role(s) in hepatocarcinogenesis among HBV-infected HCC patients.
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发表时间：
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