Subversion of Cellular Autophagy Machinery by Hepatitis B Virus for Viral Envelopment
Subversion of Cellular Autophagy Machinery by Hepatitis B Virus for Viral Envelopment
复制标题
DOI：
10.1128/jvi.02627-10
复制
发表时间：
2011-07-01
影响因子：
5.4
通讯作者：
Yuan, Zhenghong
中科院分区：
文献类型：
--
作者：
Li, Jianhua;Liu, Yinghui;Yuan, Zhenghong
自噬是一种保守的真核生物机制，通过溶酶体降解途径介导长寿命细胞质大分子和受损细胞器的清除。最近，大量的研究报道，病毒感染可能与自噬过程有复杂的相互联系。本文报道的研究结果表明，B型肝炎病毒（HBV）可增强肝癌细胞的自噬过程，而不促进溶酶体对蛋白质的降解。突变分析表明，HBV小表面蛋白（SHBs）是HBV诱导自噬所必需的。SHBs的过度表达足以诱导自噬。此外，SHB还能引发未折叠蛋白反应（UPR），阻断UPR信号通路可抑制SHB诱导的LC 3-I脂化。同时，研究了自噬体在HBV复制中的作用。自噬抑制剂3-甲基腺嘌呤（3-MA）或靶向自噬体形成关键基因（Beclin 1和ATG 5基因）的小干扰RNA双链体抑制自噬体形成显着抑制HBV的产生，雷帕霉素或饥饿诱导自噬极大地促进了HBV的产生。此外，有证据表明自噬机制是HBV抑制所必需的，但不是HBV释放效率所必需的。最后，SHBs部分共定位并与自噬蛋白LC 3相互作用。总之，这些结果表明，宿主的自噬机制在HBV感染期间被激活以增强HBV复制。
Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. The findings reported here demonstrate that hepatitis B virus (HBV) can enhance the autophagic process in hepatoma cells without promoting protein degradation by the lysosome. Mutation analysis showed that HBV small surface protein (SHBs) was required for HBV to induce autophagy. The overexpression of SHBs was sufficient to induce autophagy. Furthermore, SHBs could trigger unfolded protein responses (UPR), and the blockage of UPR signaling pathways abrogated the SHB-induced lipidation of LC3-I. Meanwhile, the role of the autophagosome in HBV replication was examined. The inhibition of autophagosome formation by the autophagy inhibitor 3-methyladenine (3-MA) or small interfering RNA duplexes targeting the genes critical for autophagosome formation (Beclin1 and ATG5 genes) markedly inhibited HBV production, and the induction of autophagy by rapamycin or starvation greatly contributed to HBV production. Furthermore, evidence was provided to suggest that the autophagy machinery was required for HBV envelopment but not for the efficiency of HBV release. Finally, SHBs partially colocalized and interacted with autophagy protein LC3. Taken together, these results suggest that the host's autophagy machinery is activated during HBV infection to enhance HBV replication.