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Sci. Signal., 19 January 2010
Vol. 3, Issue 105, p. ra5
[DOI: 10.1126/scisignal.2000510]

RESEARCH ARTICLES

Attenuation of Rabies Virulence: Takeover by the Cytoplasmic Domain of Its Envelope Protein

Christophe Préhaud1,2,3*, Nicolas Wolff1,4,5, Elouan Terrien1,4,5, Mireille Lafage1,2,3, Françoise Mégret1,2,3, Nicolas Babault1,4,5, Florence Cordier1,4,5, Gene S. Tan6, Elodie Maitrepierre1,4,5, Pauline Ménager1,2,3, Damien Chopy1,2,3, Sylviane Hoos1,7,5, Patrick England1,7,5, Muriel Delepierre1,4,5, Matthias J. Schnell6, Henri Buc1, and Monique Lafon1,2,3{dagger}

1 Institut Pasteur, 75724 Paris, France.
2 Unité de Neuroimmunologie Virale, Département de Virologie, Institut Pasteur, 75724 Paris, France.
3 CNRS URA 3015, Institut Pasteur, 75724 Paris, France.
4 Unité de Résonance Magnétique Nucléaire des Biomolécules, Département de Biologie Structurale et Chimie, Institut Pasteur, 75724 Paris, France.
5 CNRS URA 2185, Institut Pasteur, 75724 Paris, France.
6 Department of Microbiology and Immunology, and Jefferson Vaccine Centre, Thomas Jefferson University, Philadelphia, PA 19107–5541, USA.
7 Plateforme de Biophysique des Macromolécules et de leurs Interactions, Institut Pasteur, 75724 Paris, France.

* The author is on a 6-month visit to Thomas Jefferson University.

Abstract: The capacity of a rabies virus to promote neuronal survival (a signature of virulence) or death (a marker of attenuation) depends on the cellular partners recruited by the PDZ-binding site (PDZ-BS) of its envelope glycoprotein (G). Neuronal survival requires the selective association of the PDZ-BS of G with the PDZ domains of two closely related serine-threonine kinases, MAST1 and MAST2. Here, we found that a single amino acid change in the PDZ-BS triggered the apoptotic death of infected neurons and enabled G to interact with additional PDZ partners, in particular the tyrosine phosphatase PTPN4. Knockdown of PTPN4 abrogated virus-mediated apoptosis. Thus, we propose that attenuation of rabies virus requires expansion of the set of host PDZ proteins with which G interacts, which interferes with the finely tuned homeostasis required for survival of the infected neuron.

{dagger} To whom correspondence should be addressed. E-mail: monique.lafon{at}pasteur.fr

Citation: C. Préhaud, N. Wolff, E. Terrien, M. Lafage, F. Mégret, N. Babault, F. Cordier, G. S. Tan, E. Maitrepierre, P. Ménager, D. Chopy, S. Hoos, P. England, M. Delepierre, M. J. Schnell, H. Buc, M. Lafon, Attenuation of Rabies Virulence: Takeover by the Cytoplasmic Domain of Its Envelope Protein. Sci. Signal. 3, ra5 (2010).

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