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

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

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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