1 key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
2 Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai, China
ABSTRACT：
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. Over-expression of SHBs was sufficient to induce autophagy. Furthermore, SHBs could trigger unfolded protein response (UPR), and blockage of UPR signaling pathways abrogated the SHBs-induced lipidation of LC3-I. Meanwhile, the role of the autophagosome in HBV replication was examined. Inhibition of autophagosome formation by the autophagy inhibitor 3-MA or small interfering RNA duplexes targeting the genes critical for autophagosome formation (Beclin1 and ATG5 genes) markedly inhibited HBV production, and 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. 作者: ms003 时间: 2015-9-5 11:30
yaoming发表于 2011-4-21 12:44
一年前PNAS上也发了一篇类有关HBV与自噬的文章：
The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication
Donna Sira, Yongjun Tiana, Wen-ling Chena, David K. Annb, Tien-Sze Benedict Yenc,1, and Jing-hsiung James Oua,2
+ Author Affiliations
aDepartment of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033;
bDepartment of Clinical and Medical Pharmacology, City of Hope National Medical Center, Duarte, CA 91010; and
cPathology Service, Veterans Affairs Medical Center, and Department of Pathology, University of California, San Francisco, CA 94121
Edited by Ding-Shinn Chen, National Taiwan University College of Medicine, Taipei, Taiwan, and approved January 8, 2010 (received for review October 2, 2009)
Abstract
Autophagy is a catabolic process by which cells remove long-lived proteins and damaged organelles for recycling. Viral infections may also induce autophagic response. Here we show that hepatitis B virus (HBV), a pathogen that chronically infects ≈350 million people globally, can enhance autophagic response in cell cultures, mouse liver, and during natural infection. This enhancement of the autophagic response is not coupled by an increase of autophagic protein degradation and is dependent on the viral X protein, which binds to and enhances the enzymatic activity of phosphatidylinositol 3-kinase class III, an enzyme critical for the initiation of autophagy. Further analysis indicates that autophagy enhances HBV DNA replication, with minimal involvement of late autophagic vacuoles in this process. Our studies thus demonstrate that a DNA virus can use autophagy to enhance its own replication and indicate the possibility of targeting the autophagic pathway for the treatment of HBV patients.
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更早的一篇：
Hepatology. 2009 Jan;49(1):60-71.
Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression.
Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, Li F, Wang Y, Tiollais P, Li T, Zhao M.
SourceState Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
Erratum in
Hepatology. 2010 Sep;52(3):1176.
Abstract
Human beclin 1 is the first identified mammalian gene to induce autophagy. It is commonly expressed at reduced levels in breast tumors; however, it is overexpressed in hepatitis B virus (HBV)-infected cancerous liver tissues. To expose the possible mechanism and biological significance of this up-regulation of beclin 1, we investigated the regulation of beclin 1 expression by HBV x protein (HBx) in hepatic or hepatoma cell lines. Here, we showed that enforced expression of HBx by transfection technology results in the up-regulation of the endogenous messenger RNA (mRNA) and protein levels of Beclin 1 in the tested cells. Using a luciferase- reporter assay, we demonstrated that HBx transactivates beclin 1 promoter activity in a dose-dependent manner. The promoter region of the beclin 1 gene identified in this study is located at nt -277/+197 and has the maximum transcriptional activity. HBx-mediated up-regulation of beclin 1 expression might be direct, that is, via its promoter. Furthermore, the cells that transiently or stably expressed HBx showed an enhanced accumulation of vacuoles carrying the autophagy marker LC3 as compared with the control cells, which was induced by nutrient starvation, indicating HBx-enhanced autophagy. Moreover, this enhanced autophagy occurred in HepG2.2.15 cells that replicate HBV and in cells transfected with HBV genomic DNA, suggesting that HBV infection also causes increased levels of autophagy under starvation conditions. Treatment of cells with beclin 1 small interfering RNA (siRNA) blocked HBx-enhanced autophagy, demonstrating that the function of HBx in influencing autophagy is Beclin 1 dependent. Conclusion: Our findings suggest a novel function of HBx in increasing autophagy through the up-regulation of beclin1 expression, and this may provide an important mechanism in HBV-infected hepatocytes growing under nutrient-deficient conditions.