泛素蛋白酶体介导的聚合酶降解抑制乙肝病毒复制

tonychant

Abstract

Cellular inhibitor of apoptosis protein 2 (cIAP2) is a potent suppressor of apoptotic cell death. We have shown previously that cIAP2 is involved in the tumor necrosis factor alpha (TNF-α)-induced ant***titis B virus (HBV) response; however, the mechanism for this antiviral effect remains unclear. In the present study, we demonstrate that cIAP2 can significantly reduce the levels of HBV DNA replication intermediates but not the total viral RNA or core protein levels. Domain-mapping analysis revealed that the carboxy-terminal domains of cIAP2 were indispensable for this anti-HBV ability and that an E3 ligase-deficient mutant of cIAP2 (termed cIAP2*) completely lost its antiviral activity. We further identified HBV polymerase as the target of cIAP2. Overexpression of cIAP2 but not cIAP2* reduced polymerase protein levels, while cIAP2 knockdown increased polymerase expression. In addition, we observed that cIAP2 promoted the degradation of the viral polymerase through a proteasome-dependent pathway. Further experiments demonstrated that cIAP2 can bind to polymerase and promote its polyubiquitylation. Finally, we found that cIAP2 downregulated the encapsidation of HBV pregenomic RNA. Taken together, these data reveal a novel mechanism for the inhibition of HBV replication by cIAP2 via acceleration of the ubiquitin-proteasome-mediated decay of polymerase and reduction of the encapsidation of HBV pregenomic RNA, making this mechanism a novel strategy for HBV therapy.

摘要 细胞抑制剂-凋亡蛋白2(cIAP2)是一种有效的凋亡细胞凋亡抑制剂。我们之前已经研究揭示cIAP2与肿瘤坏死因子α(TNF-α)诱导的抗乙肝病毒(HBV)反应有关；然而，对于这种抗病毒的机制依然不是很清楚。在此项研究中，我们发现cIAP2可以显著降低HBV DNA复制的中间体水平，而不是降低整个病毒RNA或者核心蛋白水平。结构域图谱分析显示cIAP2的羧基端区域对于抗乙肝病毒是必不可少的，而cIAP2的突变体-E3连接酶缺陷(命名为cIAP2*)则完全失去抗病毒能力。我们进一步证实cIAP2的靶点为HBV聚合酶。过表达cIAP2而非cIAP2*会降低聚合酶蛋白水平，而cIAP2敲除则会增加聚合酶的表达。此外我们发现cIAP2通过蛋白酶体依赖途径促进病毒聚合酶的降解。进一步的实验揭示cIAP2能结合聚合酶并促进聚合酶的泛素化。最后，我们还发现cIAP2下调HBV前基因组RNA的衣壳化。综合起来，这些数据揭示一种新的抑制HBV复制的机制，那就是通过cIAP2加快泛素蛋白酶体介导的聚合酶降解和减少HBV前基因组RNA的衣壳化，这也使得该种机制成为HBV治疗的一种新的策略。



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