The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B
The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B
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乙型肝炎病毒编码的X蛋白的抗切除活性
DOI：
10.1002/hep.30571
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发表时间：
2019-06-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Cong
中科院分区：
文献类型：
--
作者：
Ren, Laifeng;Zeng, Ming;Liu, Cong
乙型肝炎病毒（HBV）的慢性感染与肝细胞癌（HCC）发病率增加有关。 HBV 编码一种癌蛋白，即乙型肝炎 x 蛋白 (HBx)，它对病毒复制至关重要，并干扰多种细胞活动，包括基因表达、组蛋白修饰和基因组稳定性。迄今为止，尚不清楚这些活动的破坏如何导致肝癌的发生。在这里，我们报告说，HBV 通过破坏 DNA 末端切除而表现出抗切除活性，从而损害同源重组 (HR) 的初始步骤。这种抗切除活性发生在经历自然病毒感染复制周期的原代人肝细胞以及具有整合的 HBV 基因组的细胞中。在七种 HBV 编码的蛋白质中，我们确定 HBx 是唯一抑制切除的病毒因子。通过破坏进化上保守的 Cullin4A 损伤特异性 DNA 结合蛋白 1-RING 型 E3 连接酶 CRL4(WDR70)，通过其 H 盒，我们发现 HBx 抑制双链断裂处赖氨酸 120 处的 H2B 单泛素化，从而降低远距离切除的效率。我们进一步表明，直接损害 H2B 单泛素化会在无胸腺小鼠中移植有缺陷的细胞时引发肿瘤发生，证实 HBx 对 CRL4（WDR70）功能的损害足以促进癌发生。最后，我们证明，与无 HBV 的 HCC 相比，人类 HBV 相关的 HCC 中明显缺乏 H2B 单泛素化，这意味着表观遗传调控和末端切除存在相应的缺陷。结论：HBx 的抗切除活性会诱导 HR 缺陷和基因组不稳定，并促进宿主肝细胞的肿瘤发生。
Chronic infection of hepatitis B virus (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein, hepatitis B x protein (HBx), that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications, and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits antiresection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This antiresection activity occurs in primary human hepatocytes undergoing a natural viral infection-replication cycle as well as in cells with integrated HBV genomes. Among the seven HBV-encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A-damage-specific DNA binding protein 1-RING type of E3 ligase, CRL4(WDR70), through its H-box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 at double-strand breaks, thus reducing the efficiency of long-range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4(WDR70) function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrate that lack of H2B monoubiquitylation is manifest in human HBV-associated HCC when compared with HBV-free HCC, implying corresponding defects of epigenetic regulation and end resection. Conclusion: The antiresection activity of HBx induces an HR defect and genomic instability and contributes to tumorigenesis of host hepatocytes.