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Journal of Virology, July 2007, p. 7504-7516, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02690-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Poliovirus Induces Bax-Dependent Cell Death Mediated by c-Jun NH₂-Terminal Kinase

Arnaud Autret,¹ Sandra Martin-Latil,¹ Laurence Mousson,¹ Aurélie Wirotius,¹ Frédéric Petit,² Damien Arnoult,² Florence Colbère-Garapin,¹ Jérôme Estaquier,^2, and Bruno Blondel^1*

Biologie des Virus Entériques,¹ Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 75724 Paris, France²

Received 6 December 2006/ Accepted 30 April 2007

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 NH₂-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.

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* Corresponding author. Mailing address: Biologie des Virus Entériques, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France. Phone: 33 1.40.61.35.90. Fax: 33 1.40.61.34.21. E-mail: bblondel{at}pasteur.fr

Published ahead of print on 9 May 2007.

Present address: INSERM V841, 94010 Créteil, France.

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Journal of Virology, July 2007, p. 7504-7516, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02690-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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