Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.
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.
Préhaud
Christophe
C
Institut Pasteur, 75724 Paris, France.
Wolff
Nicolas
N
Terrien
Elouan
E
Lafage
Mireille
M
Mégret
Françoise
F
Babault
Nicolas
N
Cordier
Florence
F
Tan
Gene S
GS
Maitrepierre
Elodie
E
Ménager
Pauline
P
Chopy
Damien
D
Hoos
Sylviane
S
England
Patrick
P
Delepierre
Muriel
M
Schnell
Matthias J
MJ
Buc
Henri
H
Lafon
Monique
M
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
D014759:Viral Envelope Proteins; D017346:Protein Serine-Threonine Kinases; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; C516659:Ptpn4 protein, mouse