Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response.
Numerous viruses including hepatitis B virus (HBV) induce endoplasmic reticulum (ER) stress, which interrupts protein folding causing accumulation of unfolded or misfolded proteins in ER. To alleviate the stress placed on ER, these proteins must be refolded or degraded by activating a specific cellular response known as ER stress response or unfolded protein response (UPR). Two UPR-specific signaling pathways involving transmembrane proteins ATF6 and XBP1 generate critical transcription factors that activate UPR-responsive genes. In this study, the role of the multifunctional regulatory protein of HBV (HBx protein) in activation of UPR was investigated. In Hep3B cells with transit or stable expression of HBx, XBP1 expression and ATF6 cleavage was observed, suggesting that the ATF6 and IRE1-XBP1 pathways were activated. Furthermore, these two pathways were also activated in HepG2.2.15 cells that constitutively replicate the intact HBV genome, and blocked at least partly by cotransfection with small interfering RNA (siRNA) expression plasmid that knocked down HBx expression. Our results clearly establish HBx as an inducer of UPR and the activator of the ATF6 and IRE1-XBP1 pathways of UPR. HBx-mediated activation of these pathways of UPR probably promote HBV replication and expression in liver cells, and contribute to liver pathogenesis, perhaps even to hepatocellular carcinoma (HCC) development.
Li
Baozong
B
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Gao
Bo
B
Ye
Linbai
L
Han
Xue
X
Wang
Wei
W
Kong
Lingbao
L
Fang
Xiaonan
X
Zeng
Yingchun
Y
Zheng
Hong
H
Li
Shanshan
S
Wu
Zhenghui
Z
Ye
Li
L
D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis*; D017918:Orthohepadnavirus; D010957:Plasmids; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; D000071717:X-Box Binding Protein 1
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C057628:hepatitis B virus X protein; D008156:Luciferases