Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level
Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level
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DOI：
10.1016/j.jhep.2014.11.028
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发表时间：
2015-04-01
影响因子：
25.7
通讯作者：
Hildt, Eberhard
中科院分区：
文献类型：
--
作者：
Peiffer, Kai-Henrik;Akhras, Sami;Hildt, Eberhard
背景与目的：HBVG型(HBVG型)以HBeAg分泌不足和HBs Ag分泌极低为特征。本研究的目的是(1)比较G和A2两种HBV型在形态发生和HBV源颗粒释放方面的差异，(2)确定与HBVG相关的致病因素。方法：采用激光共聚焦扫描显微镜、Western印迹、实时荧光定量聚合酶链式反应、密度梯度离心法和电子显微镜对表达HBVG和HBVA的肝癌细胞和感染的HepaRG细胞进行分析。结果：在HBVG复制细胞中，病毒颗粒的释放没有受到影响，但亚病毒颗粒的分泌受到了抑制，尽管它们的产量很高。这些亚病毒颗粒密度增加，形态以丝状为主，聚集在内质网。G基因的PreS1PreS2结构域形成聚集体，导致内质网表面抗原分泌受阻，导致LHBs转录激活功能降低。细胞内积聚的乙肝表面抗原和细胞保护性转录因子Nrf2的诱导受阻会导致ROI水平升高。这导致JNK的激活，从而导致IRS-1的丝氨酸磷酸化，这被认为是削弱胰岛素信号转导的肝脏再生的关键因素。结论：尽管能够释放病毒颗粒，但在表达HBVG的细胞中，亚病毒颗粒的分泌受到损害，从而导致ER应激。同时，乙肝病毒诱导的Nrf2活性减弱，从而导致ROI失活能力的降低。这可能与基因特异的发病机制有关。(C)2015年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
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 HBVderived 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 cyto-protective 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.