Mitochondrially Associated Hepatitis B Virus X Protein Constitutively Activates Transcription Factors STAT-3 and NF-κB via Oxidative Stress

HBx公司 生物 线粒体 转录因子 细胞生物学 氧化应激 分子生物学 线粒体ROS 乙型肝炎病毒 生物化学 病毒 病毒学 基因
作者
Gulam Waris,Kyung-Won Huh,Aleem Siddiqui
出处
期刊:Molecular and Cellular Biology [Taylor & Francis]
卷期号:21 (22): 7721-7730 被引量:310
标识
DOI:10.1128/mcb.21.22.7721-7730.2001
摘要

The hepatitis B virus X protein (HBx) plays essential roles in viral replication and the generation of hepatocellular carcinoma. In spite of a large number of suggestive cellular targets and functions, a clear picture of its mechanism(s) of action has remained elusive. In this report, we continue to characterize its recently described mitochondrial association and further examine its impact on mitochondrial functions. HBx was previously shown to bind to a voltage-dependent anion channel (VDAC3) and alter the mitochondrial transmembrane potential (ΔΨm). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-κB. This induction of activation was sensitive to the antioxidantsN-acetyl l-cysteine and pyrrolidine dithiocarbamate, as well as to overexpression of Mn-superoxide dismutase. These results therefore implicate a potential role of reactive oxygen species (ROS) in a process that ultimately leads to the activation of STAT-3 and NF-κB. Evidence is also presented for the HBx-induced generation of ROS. The ability of HBx to induce the activation of STAT-3 and NF-κB was demonstrated by mobility shift and reporter gene expression assays with lysates from HBx-transfected HepG2 cells. A C-terminal HBx deletion mutant, HBxΔ99, failed to bind VDAC3 and activate STAT-3 and NF-κB. These studies shed new light on the physiological significance of HBx's mitochondrial association and its role in inducing oxidative stress which can contribute to the liver disease pathogenesis associated with the hepatitis B virus infection.
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