Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.

Christophe Préhaud (1) , Nicolas Wolff (2) , Elouan Terrien (2) , Mireille Lafage (1) , Françoise Mégret (1) , Nicolas Babault (2) , Florence Cordier (2) , Gene S. Tan (3) , Elodie Maitrepierre (2) , Pauline Ménager (1) , Damien Chopy (1) , Sylviane Hoos (4) , Patrick England (4) , Muriel Delepierre (2) , Matthias J. Schnell (3) , Henri Prof Buc (5) , Monique Lafon (1)

1 Neuro-Immunologie Virale
2 Résonance Magnétique Nucléaire des Biomolécules
3 Department of Microbiology and Immunology
4 Biophysique des Macromolécules et de leurs Interactions
5 IP - Institut Pasteur [Paris]

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.

Domains: Microbiology and Parasitology

Christophe Préhaud, Nicolas Wolff, Elouan Terrien, Mireille Lafage, Françoise Mégret, et al.. Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.. Science Signaling, 2010, 3 (105), pp.ra5. ⟨10.1126/scisignal.2000510⟩. ⟨pasteur-00460584⟩