Chromatin remodelling factor BAF155 protects hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation
Chromatin remodelling factor BAF155 protects hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation
复制标题
染色质重塑因子 BAF155 保护乙型肝炎病毒 X 蛋白 (HBx) 免受泛素依赖性蛋白酶体降解
DOI：
10.1080/22221751.2019.1666661
复制
发表时间：
2019-01-01
影响因子：
13.2
通讯作者：
Lin, Xu
中科院分区：
文献类型：
--
作者：
Chen, Huijing;Zhang, Yi;Lin, Xu
HBx 是一种寿命较短的蛋白质，其快速周转主要受泛素依赖性蛋白酶体降解途径的调节。我们之前的工作确定 BAF155 是 HBx 结合伙伴之一。由于 BAF155 已被证明可以通过减弱 SWI/SNF 染色质重塑复合物的其他成员的蛋白酶体降解来稳定它们，因此我们提出 BAF155 也可能有助于以蛋白酶体依赖性方式稳定 HBx 蛋白。在此，我们报道 BAF155 通过与 20S 蛋白酶体亚基 PSMA7 竞争与 HBx 结合，保护乙型肝炎病毒 X 蛋白 (HBx) 免受泛素依赖性蛋白酶体降解。发现 BAF155 通过其 SANT 结构域与氨基酸残基 81 和 120 之间的 HBx 区域结合而直接与 HBx 相互作用。全长 BAF155 或 SANT 结构域的表达增加了 HBx 蛋白水平，而 siRNA 介导的内源 BAF155 敲低降低了 HBx 蛋白水平。 BAF155 增加的 HBx 稳定性和稳态水平可归因于抑制泛素依赖性和 PSMA7 介导的蛋白质降解。因此，BAF155的过表达增强了HBx的转录反式激活功能，激活原癌基因表达并抑制肝癌细胞克隆形成。这些结果表明BAF155在HBx的泛素非依赖性降解中发挥重要作用，这可能与HBV相关HCC的发病机制和癌变有关。
HBx is a short-lived protein whose rapid turnover is mainly regulated by ubiquitin-dependent proteasomal degradation pathways. Our prior work identified BAF155 to be one of the HBx binding partners. Since BAF155 has been shown to stabilize other members of the SWI/SNF chromatin remodelling complex by attenuating their proteasomal degradation, we proposed that BAF155 might also contribute to stabilizing HBx protein in a proteasome-dependent manner. Here we report that BAF155 protected hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation by competing with the 20S proteasome subunit PSMA7 to bind to HBx. BAF155 was found to directly interact with HBx via binding of its SANT domain to the HBx region between amino acid residues 81 and 120. Expression of either full-length BAF155 or SANT domain increased HBx protein levels whereas siRNA-mediated knockdown of endogenous BAF155 reduced HBx protein levels. Increased HBx stability and steady-state level by BAF155 were attributable to inhibition of ubiquitin-independent and PSMA7-mediated protein degradation. Consequently, overexpression of BAF155 enhanced the transcriptional transactivation function of HBx, activated protooncogene expression and inhibited hepatoma cell clonogenicity. These results suggest that BAF155 plays important roles in ubiquitin-independent degradation of HBx, which may be related to the pathogenesis and carcinogenesis of HBV-associated HCC.