Deubiquitylation of hepatitis B virus X protein (HBx) by ubiquitin-specific peptidase 15 (USP15) increases HBx stability and its transactivation activity.
Deubiquitylation of hepatitis B virus X protein (HBx) by ubiquitin-specific peptidase 15 (USP15) increases HBx stability and its transactivation activity.
复制标题
泛素特异性肽酶 15 (USP15) 对乙型肝炎病毒 X 蛋白 (HBx) 的去泛素化可增加 HBx 的稳定性及其反式激活活性
DOI：
10.1038/srep40246
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发表时间：
2017-01-11
影响因子：
4.6
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Su ZJ;Cao JS;Wu YF;Chen WN;Lin X;Wu YL;Lin X
乙型肝炎病毒X蛋白（HBx）在病毒复制和肝细胞癌的发展中起重要作用。HBx是一种快速转化蛋白，泛素-蛋白酶体途径被认为会影响HBx的稳定性，因为用蛋白酶体抑制剂治疗会增加HBx蛋白的水平，并导致HBx多泛素化形式的积累。众所周知，去泛素酶（Deubiquitinases, DUBs）的作用是去除蛋白质中的泛素部分，从而逆转其稳定性和/或活性。然而，尚无关于dub参与调节泛素化依赖性蛋白酶体降解HBx蛋白的信息。本研究发现去泛素化酶USP15是HBx蛋白水平的关键调节因子。发现USP15通过与HBx氨基酸残基51和80之间的HBx区域结合直接与HBx相互作用。USP15以剂量依赖的方式增加HBx蛋白水平，sirna介导的内源性USP15敲低降低HBx蛋白水平。USP15增加HBx的稳定性和稳态水平是由于HBx泛素化和蛋白酶体降解的减少。重要的是，HBx的转录激活功能通过USP15的过表达而增强。这些结果表明，USP15在稳定HBx中发挥重要作用，进而影响HBx的生物学功能。
Hepatitis B virus X protein (HBx) plays important roles in viral replication and the development of hepatocellular carcinoma. HBx is a rapid turnover protein and ubiquitin-proteasome pathway has been suggested to influence HBx stability as treatment with proteasome inhibitors increases the levels of HBx protein and causes accumulation of the polyubiquitinated forms of HBx. Deubiquitinases (DUBs) are known to act by removing ubiquitin moieties from proteins and thereby reverse their stability and/or activity. However, no information is available regarding the involvement of DUBs in regulation of ubiquitylation-dependent proteasomal degradation of HBx protein. This study identified the deubiquitylating enzyme USP15 as a critical regulator of HBx protein level. USP15 was found to directly interact with HBx via binding to the HBx region between amino acid residues 51 and 80. USP15 increased HBx protein levels in a dose-dependent manner and siRNA-mediated knockdown of endogenous USP15 reduced HBx protein levels. Increased HBx stability and steady-state level by USP15 were attributable to reduced HBx ubiquitination and proteasomal degradation. Importantly, the transcriptional transactivation function of HBx is enhanced by overexpression of USP15. These results suggest that USP15 plays an essential role in stabilizing HBx and subsequently affects the biological function of HBx.