title: Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.
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.
authors.affiliation: Institut Pasteur, 75724 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Préhaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wolff
authors.forename: Elouan
authors.initials: E
authors.lastname: Terrien
authors.forename: Mireille
authors.initials: M
authors.lastname: Lafage
authors.forename: Françoise
authors.initials: F
authors.lastname: Mégret
authors.forename: Nicolas
authors.initials: N
authors.lastname: Babault
authors.forename: Florence
authors.initials: F
authors.lastname: Cordier
authors.forename: Gene S
authors.initials: GS
authors.lastname: Tan
authors.forename: Elodie
authors.initials: E
authors.lastname: Maitrepierre
authors.forename: Pauline
authors.initials: P
authors.lastname: Ménager
authors.forename: Damien
authors.initials: D
authors.lastname: Chopy
authors.forename: Sylviane
authors.initials: S
authors.lastname: Hoos
authors.forename: Patrick
authors.initials: P
authors.lastname: England
authors.forename: Muriel
authors.initials: M
authors.lastname: Delepierre
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Schnell
authors.forename: Henri
authors.initials: H
authors.lastname: Buc
authors.forename: Monique
authors.initials: M
authors.lastname: Lafon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D003593:Cytoplasm; D051379:Mice; D009474:Neurons / Q000821:virology; D054731:PDZ Domains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; D011818:Rabies; D011820:Rabies virus / Q000472:pathogenicity*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014774:Virulence
chemical_list: D014759:Viral Envelope Proteins; D017346:Protein Serine-Threonine Kinases; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; C516659:Ptpn4 protein, mouse