Poliovirus induces Bax-dependent cell death mediated by c-Jun NH2-terminal kinase.
Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH(2)-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.
Autret
Arnaud
A
Biologie des Virus Entériques, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France.
Martin-Latil
Sandra
S
Mousson
Laurence
L
Wirotius
Aurélie
A
Petit
Frédéric
F
Arnoult
Damien
D
Colbère-Garapin
Florence
F
Estaquier
Jérôme
J
Blondel
Bruno
B
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000821:virology; D010766:Phosphorylation; D017955:Poliovirus / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein / Q000502:physiology*
D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases