Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B
Abstract
Ground glass hepatocytes (GGHs), a histological hallmark of chronic hepatitis B virus (HBV) infection, contain excessive hepatitis surface antigen (HBsAg) in the endoplasmic reticulum (ER), which is linked to unfolded protein response (UPR). The mechanism by which HBV activates UPR has not been fully defined. To investigate this, HepG2-NTCP cells and primary human hepatocytes (PHHs) were either infected with HBV or transduced with adenoviral vectors expressing replication-competent HBV genome or individual HBV genes. UPR markers were evaluated by qPCR, Western blotting, and immunofluorescence. Apoptosis and cell viability were measured by Caspase-3/7 and ATPlite assay respectively. We found that UPR markers were induced by the overexpression of HBsAg in HepG2-NTCP cells and PHHs. Elevation of UPR-induced genes showed a dose-dependent correlation with HBsAg levels. In HBV-infected livers, GGHs also demonstrated excessive accumulation of HBsAg associated with increased BIP/GRP78 staining, a marker of UPR. Prolonged activation of UPR by HBsAg overexpression induced signs of apoptosis. Overexpression of HBsAg can induce ER stress through protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in vitro, and may be linked to the appearance of GGHs. The activation of UPR by HBsAg may sensitize hepatocytes to cell death and result in possible subsequent cellular changes leadingmore »
- Authors:
-
[2];
[4];
[2]
- Peking Univ. Health Science Center, Beijing (China). School of Basic Medical Sciences. Dept. of Microbiology and Infectious Disease Center; National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Diabetes and Digestive and Kidney Diseases. Liver Diseases Branch
- National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Diabetes and Digestive and Kidney Diseases. Liver Diseases Branch
- National Inst. of Health (NIH), Bethesda, MD (United States). National Cancer Inst. Lab. of Pathology
- Peking Univ. Health Science Center, Beijing (China). School of Basic Medical Sciences. Dept. of Microbiology and Infectious Disease Center
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1628586
- Grant/Contract Number:
- SC0014664
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Viruses
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 4; Journal ID: ISSN 1999-4915
- Publisher:
- MDPI
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Virology; liver disease; chronic hepatitis B; endoplasmic reticulum stress; ground glass hepatocyte; apoptosis; hepatocellular carcinoma
Citation Formats
Li, Yao, Xia, Yuchen, Cheng, Xiaoming, Kleiner, David E., Hewitt, Stephen M., Sproch, Julia, Li, Tong, Zhuang, Hui, and Liang, T. Jake. Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B. United States: N. p., 2019.
Web. doi:10.3390/v11040386.
Li, Yao, Xia, Yuchen, Cheng, Xiaoming, Kleiner, David E., Hewitt, Stephen M., Sproch, Julia, Li, Tong, Zhuang, Hui, & Liang, T. Jake. Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B. United States. https://doi.org/10.3390/v11040386
Li, Yao, Xia, Yuchen, Cheng, Xiaoming, Kleiner, David E., Hewitt, Stephen M., Sproch, Julia, Li, Tong, Zhuang, Hui, and Liang, T. Jake. Thu .
"Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B". United States. https://doi.org/10.3390/v11040386. https://www.osti.gov/servlets/purl/1628586.
@article{osti_1628586,
title = {Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B},
author = {Li, Yao and Xia, Yuchen and Cheng, Xiaoming and Kleiner, David E. and Hewitt, Stephen M. and Sproch, Julia and Li, Tong and Zhuang, Hui and Liang, T. Jake},
abstractNote = {Ground glass hepatocytes (GGHs), a histological hallmark of chronic hepatitis B virus (HBV) infection, contain excessive hepatitis surface antigen (HBsAg) in the endoplasmic reticulum (ER), which is linked to unfolded protein response (UPR). The mechanism by which HBV activates UPR has not been fully defined. To investigate this, HepG2-NTCP cells and primary human hepatocytes (PHHs) were either infected with HBV or transduced with adenoviral vectors expressing replication-competent HBV genome or individual HBV genes. UPR markers were evaluated by qPCR, Western blotting, and immunofluorescence. Apoptosis and cell viability were measured by Caspase-3/7 and ATPlite assay respectively. We found that UPR markers were induced by the overexpression of HBsAg in HepG2-NTCP cells and PHHs. Elevation of UPR-induced genes showed a dose-dependent correlation with HBsAg levels. In HBV-infected livers, GGHs also demonstrated excessive accumulation of HBsAg associated with increased BIP/GRP78 staining, a marker of UPR. Prolonged activation of UPR by HBsAg overexpression induced signs of apoptosis. Overexpression of HBsAg can induce ER stress through protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in vitro, and may be linked to the appearance of GGHs. The activation of UPR by HBsAg may sensitize hepatocytes to cell death and result in possible subsequent cellular changes leading to a premalignant phenotype.},
doi = {10.3390/v11040386},
journal = {Viruses},
number = 4,
volume = 11,
place = {United States},
year = {Thu Apr 25 00:00:00 EDT 2019},
month = {Thu Apr 25 00:00:00 EDT 2019}
}
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Figure 1: Activation of PERK pathway genes by HBsAg overexpression. (A) HepG2-NTCP cells and (B) primary human hepatocyte cells were transduced with recombinant AdVs in triplicate (MOI of 1). Protein transportation inhibitor (PTI) was used as a positive control. mRNAs of PERK genes were determined by RT-qPCR three days aftermore »
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