Antiapoptotic regulation by hepatitis C virus core protein through up-regulation of inhibitor of caspase-activated DNase.
The hepatitis C virus (HCV) core protein is considered to influence multiple cellular processes. We developed a human hepatoblastoma HepG2-derived inducible cell line, Hep191, which allows tightly regulated expression of the core protein at relatively low but physiological levels under control of the ecdysone-regulated promoter. By transcriptional profiling, we identified differentially expressed genes, some of which are involved in cell growth or apoptosis such as inhibitor of caspase-activated DNase (ICAD), defender against cell death 1, tumor necrosis factor (TNF) receptor 1, and cytochrome c oxidase subunit VIII. Furthermore, we found that core protein expression increases a steady-state level of ICAD protein, possibly through enhancing its promoter activity, and inhibits caspase-3 activity induced by anti-Fas antibody. Since Fas- or TNF-mediated DNA fragmentation is suppressed in the core-induced Hep191 cells, these findings suggest that expression of HCV core at physiological levels confers blocking activity of caspase-activated DNase and consequently inhibiting apoptotic cell death.
Sacco
Rodolfo
R
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
Tsutsumi
Takeya
T
Suzuki
Ryosuke
R
Otsuka
Motoyuki
M
Aizaki
Hideki
H
Sakamoto
Shinichiro
S
Matsuda
Mami
M
Seki
Naohiko
N
Matsuura
Yoshiharu
Y
Miyamura
Tatsuo
T
Suzuki
Tetsuro
T
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D011506:Proteins; D014758:Viral Core Proteins; C109664:caspase-activated DNase inhibitor; C069130:nucleocapsid protein, Hepatitis C virus; D003851:Deoxyribonucleases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases