Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome/multivesicular body axis.

Abstract

BACKGROUND AND AIMS:

HBV infection has been reported to trigger endoplasmic reticulum (ER) stress and initiate autophagy. However, how ER stress and autophagy influence HBV production remains elusive. Here, we studied the effect of tunicamycin (TM), an N-glycosylation inhibitor and ER stress inducer, on HBV replication and secretion and examined the underlying mechanisms.

APPROACH AND RESULTS:

Protein disulfide isomerase (an ER marker), microtubule-associated protein 1 light chain 3 beta (an autophagosome [AP] marker), and sequestosome-1 (a typical cargo for autophagic degradation) expression were tested in liver tissues of patients with chronic HBV infection and hepatoma cell lines. The role of TM treatment in HBV production and trafficking was examined in hepatoma cell lines. TM treatment that mimics HBV infection triggered ER stress and increased AP formation, resulting in enhanced HBV replication and secretion of subviral particles (SVPs) and naked capsids. Additionally, TM reduced the number of early endosomes and HBsAg localization in this compartment, causing HBsAg/SVPs to accumulate in the ER. Thus, TM-induced AP formation serves as an alternative pathway for HBsAg/SVP trafficking. Importantly, TM inhibited AP-lysosome fusion, accompanied by enhanced AP/late endosome (LE)/multivesicular body fusion, to release HBsAg/SVPs through, or along with, exosome release. Notably, TM treatment inhibited HBsAg glycosylation, resulting in impairment of HBV virions' envelopment and secretion, but it was not critical for HBsAg/SVP trafficking in our cell systems.

CONCLUSIONS:

TM-induced ER stress and autophagic flux promoted HBV replication and the release of SVPs and naked capsids through the AP-LE/MVB axis.

• Authors: Xueyu Wang, Zhiqiang Wei, Bin Cheng, Jia Li, Yulin He, Tingyu Lan, Thekla Kemper, Yong Lin, Bin Jiang, Yongfang Jiang, Zhongji Meng, Mengji Lu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 2 Pg. 438-454 (02 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34580902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Antiviral Agents
• Hepatitis B Surface Antigens
• MAP1LC3B protein, human
• Microtubule-Associated Proteins
• SQSTM1 protein, human
• Sequestosome-1 Protein
• Tunicamycin
• Protein Disulfide-Isomerases

Topics

• Antiviral Agents (pharmacology)
• Autophagosomes (drug effects)
• Autophagy (drug effects)
• Capsid
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Endosomes (drug effects)
• Glycosylation (drug effects)
• Hepatitis B Surface Antigens (metabolism)
• Hepatitis B virus (physiology)
• Hepatitis B, Chronic (metabolism, physiopathology)
• Humans
• Liver Neoplasms (metabolism)
• Lysosomes (drug effects)
• Microtubule-Associated Proteins (metabolism)
• Multivesicular Bodies
• Protein Disulfide-Isomerases (metabolism)
• Sequestosome-1 Protein (metabolism)
• Tunicamycin (pharmacology)
• Virion
• Virus Replication