Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B

Li, Yao; Xia, Yuchen; Cheng, Xiaoming; Kleiner, David E.; Hewitt, Stephen M.; Sproch, Julia; Li, Tong; Zhuang, Hui; Liang, T. Jake

doi:10.3390/v11040386

Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B

Journal Article · Thu Apr 25 00:00:00 EDT 2019 · Viruses

DOI:https://doi.org/10.3390/v11040386· OSTI ID:1628586

Li, Yao ^[1]; ^[2]; Cheng, Xiaoming ^[2]; Kleiner, David E. ^[3]; Hewitt, Stephen M. ^[3]; Sproch, Julia ^[2]; ^[4]; Zhuang, Hui ^[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; DOE/OSTI
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

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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1628586

Journal Information:: Viruses, Journal Name: Viruses Journal Issue: 4 Vol. 11; ISSN 1999-4915

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

References (58)

Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes Wang, Hui-Ching; Chang, Wen-Tsan; Chang, Wen-Wei Hepatology, Vol. 41, Issue 4 https://doi.org/10.1002/hep.20615	journal	January 2005
Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages: Cheng et al. Cheng, Xiaoming; Xia, Yuchen; Serti, Elisavet Hepatology, Vol. 66, Issue 6 https://doi.org/10.1002/hep.29348	journal	November 2017
Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance Terrault, Norah A.; Lok, Anna S. F.; McMahon, Brian J. Hepatology, Vol. 67, Issue 4 https://doi.org/10.1002/hep.29800	journal	March 2018
Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins Gerets, H. H. J.; Tilmant, K.; Gerin, B. Cell Biology and Toxicology, Vol. 28, Issue 2 https://doi.org/10.1007/s10565-011-9208-4	journal	January 2012
Hair Follicle Melanocytes Initiate Autoimmunity in Alopecia Areata: a Trigger Point Xie, Bo; Sun, Jiayi; Song, Xiuzu Clinical Reviews in Allergy & Immunology, Vol. 63, Issue 3 https://doi.org/10.1007/s12016-022-08954-w	journal	September 2022
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer Cubillos-Ruiz, Juan R.; Bettigole, Sarah E.; Glimcher, Laurie H. Cell, Vol. 168, Issue 4 https://doi.org/10.1016/j.cell.2016.12.004	journal	February 2017
Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis Wu, Han-Chieh; Tsai, Hung-Wen; Teng, Chiao-Fang Human Pathology, Vol. 45, Issue 6 https://doi.org/10.1016/j.humpath.2013.10.039	journal	June 2014
Endoplasmic reticulum stress in liver disease Malhi, Harmeet; Kaufman, Randal J. Journal of Hepatology, Vol. 54, Issue 4 https://doi.org/10.1016/j.jhep.2010.11.005	journal	April 2011
Overview of hepatitis B viral replication and genetic variability Tong, Shuping; Revill, Peter Journal of Hepatology, Vol. 64, Issue 1 https://doi.org/10.1016/j.jhep.2016.01.027	journal	April 2016
Mechanisms of HBV-induced hepatocellular carcinoma Levrero, Massimo; Zucman-Rossi, Jessica Journal of Hepatology, Vol. 64, Issue 1 https://doi.org/10.1016/j.jhep.2016.02.021	journal	April 2016
EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection Lampertico, Pietro; Agarwal, Kosh; Berg, Thomas Journal of Hepatology, Vol. 67, Issue 2 https://doi.org/10.1016/j.jhep.2017.03.021	journal	August 2017
Diverse virological, histopathological and prognostic implications of seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection Su, Ih-Jen; Lai, Ming-Yang; Hsu, Hey-Chi Journal of Hepatology, Vol. 3, Issue 2 https://doi.org/10.1016/s0168-8278(86)80024-1	journal	January 1986
Protein misfolding in the endoplasmic reticulum as a conduit to human disease Wang, Miao; Kaufman, Randal J. Nature, Vol. 529, Issue 7586 https://doi.org/10.1038/nature17041	journal	January 2016
Roles of CHOP/GADD153 in endoplasmic reticulum stress Oyadomari, S.; Mori, M. Cell Death & Differentiation, Vol. 11, Issue 4 https://doi.org/10.1038/sj.cdd.4401373	journal	December 2003
Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis Xia, Yuchen; Stadler, Daniela; Lucifora, Julie Gastroenterology, Vol. 150, Issue 1 https://doi.org/10.1053/j.gastro.2015.09.026	journal	January 2016
Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Chisari, F. V.; Filippi, P.; Buras, J. Proceedings of the National Academy of Sciences, Vol. 84, Issue 19 https://doi.org/10.1073/pnas.84.19.6909	journal	October 1987
X-gene Product of Hepatitis B Virus Induces Apoptosis in Liver Cells Kim, Hongtae; Lee, Hyunsook; Yun, Yungdae Journal of Biological Chemistry, Vol. 273, Issue 1 https://doi.org/10.1074/jbc.273.1.381	journal	January 1998
AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis Roy, H. K. Carcinogenesis, Vol. 23, Issue 1 https://doi.org/10.1093/carcin/23.1.201	journal	January 2002
Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage Hsieh, Y. -H. Carcinogenesis, Vol. 25, Issue 10 https://doi.org/10.1093/carcin/bgh207	journal	June 2004
Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype Xia, Yuchen; Cheng, Xiaoming; Li, Yao Journal of Virology, Vol. 92, Issue 19 https://doi.org/10.1128/jvi.00722-18	journal	July 2018
Characterization of the Intracellular Deproteinized Relaxed Circular DNA of Hepatitis B Virus: an Intermediate of Covalently Closed Circular DNA Formation Guo, Haitao; Jiang, Dong; Zhou, Tianlun Journal of Virology, Vol. 81, Issue 22 https://doi.org/10.1128/jvi.01123-07	journal	September 2007
Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway Liu, Ningning; Jiao, Tong; Huang, Yan Journal of Virology, Vol. 89, Issue 5 https://doi.org/10.1128/jvi.02784-14	journal	December 2014
Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum Xu, Z.; Jensen, G.; Yen, T. S. Journal of Virology, Vol. 71, Issue 10 https://doi.org/10.1128/jvi.71.10.7387-7392.1997	journal	October 1997
Transfer of Hepatitis B Virus Genome by Adenovirus Vectors into Cultured Cells and Mice: Crossing the Species Barrier Sprinzl, Martin Franz; Oberwinkler, Heike; Schaller, Heinz Journal of Virology, Vol. 75, Issue 11 https://doi.org/10.1128/jvi.75.11.5108-5118.2001	journal	June 2001
Inhibition of Cellular Proteasome Activities Enhances Hepadnavirus Replication in an HBX-Dependent Manner Zhang, Zhensheng; Protzer, Ulrike; Hu, Zongyi Journal of Virology, Vol. 78, Issue 9 https://doi.org/10.1128/jvi.78.9.4566-4572.2004	journal	May 2004
mTOR and P70 S6 Kinase Expression in Primary Liver Neoplasms Sahin, F. Clinical Cancer Research, Vol. 10, Issue 24 https://doi.org/10.1158/1078-0432.ccr-04-0941	journal	December 2004
Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis Kim, Seong-Jun; Khan, Mohsin; Quan, Jun PLoS Pathogens, Vol. 9, Issue 12 https://doi.org/10.1371/journal.ppat.1003722	journal	December 2013
Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma Tsai, Hung-Wen; Lin, Yih-Jyh; Wu, Han-Chieh Oncotarget, Vol. 7, Issue 19 https://doi.org/10.18632/oncotarget.8388	journal	March 2016
Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate Corazzari, Marco; Gagliardi, Mara; Fimia, Gian Maria Frontiers in Oncology, Vol. 7 https://doi.org/10.3389/fonc.2017.00078	journal	April 2017
Ground glass hepatocytes provide targets for therapy or prevention of hepatitis B virus-related hepatocellular carcinoma Chang, Hong-Yi; Tsai, Hung-Wen; Teng, Chiao-Fang AIMS Medical Science, Vol. 5, Issue 2 https://doi.org/10.3934/medsci.2018.2.90	journal	January 2018
Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance Terrault, Norah A.; Lok, Anna S. F.; McMahon, Brian J. Clinical Liver Disease, Vol. 12, Issue 1 https://doi.org/10.1002/cld.728	journal	July 2018
Correlation of hepatocyte HBsAg expression with virus replication and liver pathology Hsu, Hey-Chi; Lai, Ming-Yang; Su, Ih-Jen Hepatology, Vol. 8, Issue 4 https://doi.org/10.1002/hep.1840080408	journal	July 1988
Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis Yang, Jui-Chu; Teng, Chiao-Fang; Wu, Han-Chieh Hepatology, Vol. 49, Issue 6 https://doi.org/10.1002/hep.22889	journal	February 2009
Hepatitis B virus X protein induces apoptosis by enhancing translocation of Bax to mitochondria Kim, Hye Jin; Kim, Sang Yong; Kim, Jinchul IUBMB Life, Vol. 60, Issue 7 https://doi.org/10.1002/iub.68	journal	July 2008
Expression of a hepatitis B virus pre-S2 deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice: Hepatomegaly and HCC in HBV pre-S2 mutant transgenic mice Teng, Yuan-Chi; Neo, Jenq Chyuan; Wu, Jaw-Ching The Journal of Pathology, Vol. 241, Issue 4 https://doi.org/10.1002/path.4850	journal	January 2017
Different Types of Ground Glass Hepatocytes in Chronic Hepatitis B Virus Infection Contain Specific Pre-S Mutants that May Induce Endoplasmic Reticulum Stress Wang, Hui-Ching; Wu, Han-Chieh; Chen, Chien-Fu The American Journal of Pathology, Vol. 163, Issue 6 https://doi.org/10.1016/S0002-9440(10)63599-7	journal	December 2003
Diverse virological, histopathological and prognostic implications of seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection Su, Ih-Jen; Lai, Ming-Yang; Hsu, Hey-Chi Journal of Hepatology, Vol. 3, Issue 2 https://doi.org/10.1016/S0168-8278(86)80024-1	journal	January 1986
Type II ground-glass hepatocytes as a marker of hepatocellular carcinoma in chronic hepatitis B Mathai, Alka Mary; Alexander, Jacob; Kuo, Fang-Ying Human Pathology, Vol. 44, Issue 8 https://doi.org/10.1016/j.humpath.2013.01.020	journal	August 2013
ER stress: Can the liver cope? Ji, Cheng; Kaplowitz, Neil Journal of Hepatology, Vol. 45, Issue 2 https://doi.org/10.1016/j.jhep.2006.06.004	journal	August 2006
The endoplasmic reticulum stress response in immunity and autoimmunity Todd, Derrick J.; Lee, Ann-Hwee; Glimcher, Laurie H. Nature Reviews Immunology, Vol. 8, Issue 9 https://doi.org/10.1038/nri2359	journal	September 2008
Signal integration in the endoplasmic reticulum unfolded protein response Ron, David; Walter, Peter Nature Reviews Molecular Cell Biology, Vol. 8, Issue 7 https://doi.org/10.1038/nrm2199	journal	July 2007
The unfolded protein response: controlling cell fate decisions under ER stress and beyond Hetz, Claudio Nature Reviews Molecular Cell Biology, Vol. 13, Issue 2 https://doi.org/10.1038/nrm3270	journal	January 2012
Evidence against in utero transmission of hepatitis B virus Zhou, Yi-Hua Nature Reviews Gastroenterology & Hepatology, Vol. 18, Issue 6 https://doi.org/10.1038/s41575-021-00455-z	journal	April 2021
Increased infiltration of regulatory T cells in hepatocellular carcinoma of patients with hepatitis B virus pre-S2 mutant Teng, Chiao-Fang; Li, Tsai-Chung; Wang, Ting Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-020-80935-5	journal	January 2021
The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver Terradillos, Olivier; de La Coste, Alix; Pollicino, Teresa Oncogene, Vol. 21, Issue 3 https://doi.org/10.1038/sj.onc.1205110	journal	January 2002
X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway Diao, Jingyu; Khine, Aye Aye; Sarangi, Farida Journal of Biological Chemistry, Vol. 276, Issue 11 https://doi.org/10.1074/jbc.M006026200	journal	November 2000
An Overview of Unfolded Protein Response Signaling and Its Role in Cancer Jain, Buddhi Prakash Cancer Biotherapy and Radiopharmaceuticals, Vol. 32, Issue 8 https://doi.org/10.1089/cbr.2017.2309	journal	October 2017
Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection Su, Ih-Jen; Wang, Hui-Ching; Wu, Han-Chieh Journal of Gastroenterology and Hepatology, Vol. 23, Issue 8pt1 https://doi.org/10.1111/j.1440-1746.2008.05348.x	journal	August 2008
Vascular Endothelial Growth Factor and Angiogenesis Hoeben, Ann; Landuyt, Bart; Highley, Martin S. Pharmacological Reviews, Vol. 56, Issue 4 https://doi.org/10.1124/pr.56.4.3	journal	December 2004
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation Walter, P.; Ron, D. Science, Vol. 334, Issue 6059 https://doi.org/10.1126/science.1209038	journal	November 2011
Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype Xia, Yuchen; Cheng, Xiaoming; Li, Yao Journal of Virology, Vol. 92, Issue 19 https://doi.org/10.1128/JVI.00722-18	journal	July 2018
Characterization of the Intracellular Deproteinized Relaxed Circular DNA of Hepatitis B Virus: an Intermediate of Covalently Closed Circular DNA Formation Guo, Haitao; Jiang, Dong; Zhou, Tianlun Journal of Virology, Vol. 81, Issue 22 https://doi.org/10.1128/JVI.01123-07	journal	September 2007
Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway Liu, Ningning; Jiao, Tong; Huang, Yan Journal of Virology, Vol. 89, Issue 5 https://doi.org/10.1128/JVI.02784-14	journal	December 2014
Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum Xu, Z.; Jensen, G.; Yen, T. S. Journal of Virology, Vol. 71, Issue 10 https://doi.org/10.1128/JVI.71.10.7387-7392.1997	journal	October 1997
Transfer of Hepatitis B Virus Genome by Adenovirus Vectors into Cultured Cells and Mice: Crossing the Species Barrier Sprinzl, Martin Franz; Oberwinkler, Heike; Schaller, Heinz Journal of Virology, Vol. 75, Issue 11 https://doi.org/10.1128/JVI.75.11.5108-5118.2001	journal	June 2001
Inhibition of Cellular Proteasome Activities Enhances Hepadnavirus Replication in an HBX-Dependent Manner Zhang, Zhensheng; Protzer, Ulrike; Hu, Zongyi Journal of Virology, Vol. 78, Issue 9 https://doi.org/10.1128/JVI.78.9.4566-4572.2004	journal	May 2004
mTOR and P70 S6 Kinase Expression in Primary Liver Neoplasms Sahin, F. Clinical Cancer Research, Vol. 10, Issue 24 https://doi.org/10.1158/1078-0432.CCR-04-0941	journal	December 2004
Overview of hepatitis B virus mutations and their implications in the management of infection Caligiuri, Patrizia World Journal of Gastroenterology, Vol. 22, Issue 1 https://doi.org/10.3748/wjg.v22.i1.145	journal	January 2016

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59 BASIC BIOLOGICAL SCIENCES
Virology
apoptosis
chronic hepatitis B
endoplasmic reticulum stress
ground glass hepatocyte
hepatocellular carcinoma
liver disease

Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B

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