tetano
Editor, Senior Moderator
Published ahead of print 7 November 2012, doi: 10.1128/JVI.02017-12 JVI.02017-12
Influenza Virus Induces Apoptosis via BAD-mediated Mitochondria Dysregulation
Anh T. Tran1,2,
John P. Cortens2,
Qiujiang Du2,
John A. Wilkins2,3,4 and
Kevin M. Coombs1,2,5,*
+ Author Affiliations
1Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada R3E 0J6
2Manitoba Centre for Proteomics and Systems Biology, Winnipeg, MB, Canada R3E 3P4
3Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
4Department of Biochemistry and Genetics, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
5Manitoba Institute for Child Health, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
ABSTRACT
Influenza virus infection results in host cell death and major tissue damage. Specific components of the apoptotic pathway, a signaling cascade that ultimately leads to cell death, are implicated in promoting influenza virus replication. BAD is a cell death regulator that constitutes a critical control point in the intrinsic apoptosis pathway, which occurs through the dysregulation of mitochondrial outer membrane permeabilization and the subsequent activation of downstream apoptogenic factors. Here we report a novel pro-viral role for the pro-apoptotic protein BAD in influenza virus replication. We show that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and that both virus replication and viral protein production are dramatically reduced, which suggests that virus-induced apoptosis is BAD-dependent. Our data showed that influenza viruses induced phosphorylation of BAD at residues S112 and S136 in a temporal manner. Viral infection also induced BAD cleavage, late in the viral lifecycle, to a truncated form that is reportedly a more potent inducer of apoptosis. We further demonstrate that knockdown of BAD resulted in reduced cytochrome c release and suppression of the intrinsic apoptotic pathway during influenza virus replication, as seen by an inhibition of caspases-3, caspase-7 and PARP cleavage. Our data indicate that influenza viruses carefully modulate the activation of the apoptotic pathway that is dependent on the regulatory function of BAD, and failure of apoptosis activation resulted in unproductive viral replication.
http://jvi.asm.org/content/early/2012/11/02/JVI.02017-12.abstract
Influenza Virus Induces Apoptosis via BAD-mediated Mitochondria Dysregulation
Anh T. Tran1,2,
John P. Cortens2,
Qiujiang Du2,
John A. Wilkins2,3,4 and
Kevin M. Coombs1,2,5,*
+ Author Affiliations
1Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada R3E 0J6
2Manitoba Centre for Proteomics and Systems Biology, Winnipeg, MB, Canada R3E 3P4
3Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
4Department of Biochemistry and Genetics, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
5Manitoba Institute for Child Health, University of Manitoba, Winnipeg, MB, Canada R3E 3P4
ABSTRACT
Influenza virus infection results in host cell death and major tissue damage. Specific components of the apoptotic pathway, a signaling cascade that ultimately leads to cell death, are implicated in promoting influenza virus replication. BAD is a cell death regulator that constitutes a critical control point in the intrinsic apoptosis pathway, which occurs through the dysregulation of mitochondrial outer membrane permeabilization and the subsequent activation of downstream apoptogenic factors. Here we report a novel pro-viral role for the pro-apoptotic protein BAD in influenza virus replication. We show that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and that both virus replication and viral protein production are dramatically reduced, which suggests that virus-induced apoptosis is BAD-dependent. Our data showed that influenza viruses induced phosphorylation of BAD at residues S112 and S136 in a temporal manner. Viral infection also induced BAD cleavage, late in the viral lifecycle, to a truncated form that is reportedly a more potent inducer of apoptosis. We further demonstrate that knockdown of BAD resulted in reduced cytochrome c release and suppression of the intrinsic apoptotic pathway during influenza virus replication, as seen by an inhibition of caspases-3, caspase-7 and PARP cleavage. Our data indicate that influenza viruses carefully modulate the activation of the apoptotic pathway that is dependent on the regulatory function of BAD, and failure of apoptosis activation resulted in unproductive viral replication.
http://jvi.asm.org/content/early/2012/11/02/JVI.02017-12.abstract