Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome/multivesicular body axis.
Hepatology
; 75(2): 438-454, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-34580902
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 ANDRESULTS:
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Antivirales
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Replicación Viral
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Tunicamicina
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Virus de la Hepatitis B
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Carcinoma Hepatocelular
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Hepatitis B Crónica
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Estrés del Retículo Endoplásmico
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Neoplasias Hepáticas
Límite:
Humans
Idioma:
En
Revista:
Hepatology
Año:
2022
Tipo del documento:
Article