Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level
| Autor: | Michael Nuebling, Christoph Sarrazin, Malin Finkernagel, Dieter Glebe, Matthias Hassemer, Gert Carra, Stefan Zeuzem, Kiyoshi Himmelsbach, Sami Akhras, Eberhard Hildt, Michael Chudy, Hauke Niekamp, Kai-Henrik Peiffer |
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| Rok vydání: | 2014 |
| Předmět: |
HBsAg
Hepatitis B virus Genotype NF-E2-Related Factor 2 Biology medicine.disease_cause Cell Line Tumor medicine Humans Secretion Hepatitis B e Antigens Differential centrifugation Hepatitis B Surface Antigens Hepatology Endoplasmic reticulum Virion virus diseases Hepatitis B Molecular biology digestive system diseases Transcription Factor AP-1 HBx HBcAg HBeAg Hepatocytes |
| Zdroj: | Journal of hepatology. 62(4) |
| ISSN: | 1600-0641 |
| Popis: | Background & Aims Hepatitis B virus genotype G (HBV/G) is characterized by a lack of HBeAg secretion and very low HBsAg secretion. This study aimed at (1) comparing HBV genotype G and A2 with respect to morphogenesis and release of HBV-derived particles, (2) characterizing factors contributing to HBV/G-associated pathogenesis. Methods HBV/G- and HBV/A-expressing hepatoma cells and infected HepaRG cells were analyzed by confocal laser scanning microscopy, Western blot, real-time PCR, density gradient centrifugation, and electron microscopy. Modulation of the transcription factors Nrf2 and AP-1 was analyzed. Results While the release of viral particles is not affected in HBV/G replicating cells, the secretion of subviral particles is impaired, although they are produced in high amounts. These subviral particles, which display an increased density and a predominantly filamentous morphology, accumulate at the endoplasmic reticulum. The PreS1PreS2 domain of genotype G, which forms aggregates, causes the block of HBsAg-secretion at the ER and leads to decreased transcriptional activator function of LHBs. Intracellular accumulation of HBsAg and impaired induction of the cytoprotective transcription factor Nrf2 lead to an elevated level of ROIs. This results in activation of JNK and as a consequence in Ser-phosphorylation of IRS-1, which is known to impair insulin signaling, a key factor for liver regeneration. Conclusions Although competent for release of viral particles, secretion of subviral particles is impaired in HBV/G expressing cells leading to ER-stress. In parallel, HBV-induced Nrf2 activation diminishes, which causes a decrease of the capacity to inactivate ROIs. This might be related to genotype-specific pathogenesis. |
| Databáze: | OpenAIRE |
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