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

Institut Pasteur, 75724 Paris, France.
Science Signaling (Impact Factor: 6.28). 01/2010; 3(105):ra5. DOI: 10.1126/scisignal.2000510
Source: PubMed


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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    • "To generate SADcvsG, the cytoplasmic domain of SADG was replaced by that of CVSG. The cytoplasmic domain of CVSG, rather than that of HEPG, was selected since the cytoplasmic domain of RVGs of attenuated strains, such as HEP-Flury, might induce cell apoptosis (Prehaud et al., 2010). PCR was utilized to replace the cytoplasmic domain of EnvARGCD glycoprotein, which originates from the SAD strain, with that of the CVS strain. "
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