Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-κB via oxidative stress

被引:287
作者
Waris, G
Huh, KW
Siddiqui, A
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Program Mol Biol, Denver, CO 80262 USA
关键词
D O I
10.1128/MCB.21.22.7721-7730.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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 (Delta psi (m)). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-kappaB. This induction of activation was sensitive to the antioxidants N-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-kappaB. Evidence is also presented for the HBx-induced generation of ROS. The ability of HBx to induce the activation of STAT-3 and NF-kappaB was demonstrated by mobility shift and reporter gene expression assays with lysates from HBx-transfected HepG2 cells. A C-terminal HBx deletion mutant, HBx Delta 99, failed to bind VDAC3 and activate STAT-3 and NF-kappaB. 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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收藏
页码:7721 / 7730
页数:10
相关论文
共 61 条
[1]   THE HEPATITIS-B VIRUS X-GENE PRODUCT TRANS-ACTIVATES BOTH RNA POLYMERASE-II AND III-PROMOTERS [J].
AUFIERO, B ;
SCHNEIDER, RJ .
EMBO JOURNAL, 1990, 9 (02) :497-504
[2]  
BEASLEY RP, 1981, LANCET, V2, P1129
[3]   Hepatitis B virus X protein interferes with cellular DNA repair [J].
Becker, SA ;
Lee, TH ;
Butel, JS ;
Slagle, BL .
JOURNAL OF VIROLOGY, 1998, 72 (01) :266-272
[4]   HEPATITIS-B VIRUS HBX PROTEIN ACTIVATES RAS-GTP COMPLEX-FORMATION AND ESTABLISHES A RAS, RAF, MAP KINASE SIGNALING CASCADE [J].
BENN, J ;
SCHNEIDER, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (22) :10350-10354
[5]   HEPATITIS-B VIRUS HBX PROTEIN DEREGULATES CELL-CYCLE CHECKPOINT CONTROLS [J].
BENN, J ;
SCHNEIDER, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (24) :11215-11219
[6]  
BENU J, 1996, J VIROL, V70, P4978
[7]   Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease [J].
Butel, JS .
CARCINOGENESIS, 2000, 21 (03) :405-426
[8]   Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes [J].
Carballo, M ;
Conde, M ;
El Bekay, R ;
Martín-Nieto, J ;
Camacho, MJ ;
Monteseirín, J ;
Conde, J ;
Bedoya, FJ ;
Sobrino, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (25) :17580-17586
[9]   THE WOODCHUCK HEPATITIS VIRUS-X GENE IS IMPORTANT FOR ESTABLISHMENT OF VIRUS-INFECTION IN WOODCHUCKS [J].
CHEN, HS ;
KANEKO, S ;
GIRONES, R ;
ANDERSON, RW ;
HORNBUCKLE, WE ;
TENNANT, BC ;
COTE, PJ ;
GERIN, JL ;
PURCELL, RH ;
MILLER, RH .
JOURNAL OF VIROLOGY, 1993, 67 (03) :1218-1226
[10]   HUMAN RPB5, A SUBUNIT SHARED BY EUKARYOTIC NUCLEAR-RNA POLYMERASES, BINDS HUMAN HEPATITIS-B VIRUS X-PROTEIN AND MAY PLAY A ROLE IN X-TRANSACTIVATION [J].
CHEONG, JH ;
YI, MK ;
LIN, Y ;
MURAKAMI, S .
EMBO JOURNAL, 1995, 14 (01) :143-150