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Molecular & Cellular Proteomics 8:2582-2594, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Glucose-regulated Protein 78 Is an Intracellular Antiviral Factor against Hepatitis B Virus^*,

Yan Ma, Jun Yu^,¶, Henry L. Y. Chan, Yang-chao Chen, Hua Wang, Ying Chen, Chu-yan Chan, Minnie Y. Y. Go, Sau-na Tsai^||, Sai-ming Ngai^||, Ka-fai To^¶,**, Joanna H. M. Tong^¶,**, Qing-Yu He, Joseph J. Y. Sung^,¶, Hsiang-fu Kung^,¶, Christopher H. K. Cheng and Ming-liang He^,,¶,¶¶

From the Stanley Ho Center for Emerging Infectious Diseases, School of Public Health and Primary Care,
Institute of Digestive Disease, Department of Medicine and Therapeutics, and
Departments of || Biology and
**Anatomical Cellular Pathology, The Chinese University of Hong Kong , Hong Kong, China,
Institute of Life and Health Engineering, Jinan University , Guangzhou 510632, China, and
School of Biomedical Sciences and
¶Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Hong Kong, China

Hepatitis B virus (HBV) infection is a global public health problem that plays a crucial role in the pathogenesis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. However, the pathogenesis of HBV infection and the mechanisms of host-virus interactions are still elusive. In this study, two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were applied to analyze the host response to HBV using an inducible HBV-producing cell line, HepAD38. Twenty-three proteins were identified as differentially expressed with glucose-regulated protein 78 (GRP78) as one of the most significantly up-regulated proteins induced by HBV replication. This induction was further confirmed in both HepAD38 and HepG2 cells transfected with HBV-producing plasmids by real time RT-PCR and Western blotting as well as in HBV-infected human liver biopsies by immunohistochemistry. Knockdown of GRP78 expression by RNA interference resulted in a significant increase of both intracellular and extracellular HBV virions in the transient HBV-producing HepG2 cells concomitant with enhanced levels of hepatitis B surface antigen and e antigen in the culture medium. Conversely overexpression of GRP78 in HepG2 cells led to HBV suppression concomitant with induction of the positive regulatory circuit of GRP78 and interferon-β1 (IFN-β1). In this connection, the IFN-β1-mediated 2',5'-oligoadenylate synthetase and RNase L signaling pathway was noted to be activated in GRP78-overexpressing HepG2 cells. Moreover GRP78 was significantly down-regulated in the livers of chronic hepatitis B patients after effective anti-HBV treatment (p = 0.019) as compared with their counterpart pretreatment liver biopsies. In conclusion, the present study demonstrates for the first time that GRP78 functions as an endogenous anti-HBV factor via the IFN-β1-2',5'-oligoadenylate synthetase-RNase L pathway in hepatocytes. Induction of hepatic GRP78 may provide a novel therapeutic approach in treating HBV infection.

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