Strategies to interfere with PDZ-mediated interactions in neurons: What we can learn from the rabies virus.
PDZ (PSD-95/Dlg/ZO-1) domains play a major role in neuronal homeostasis in which they act as scaffold domains regulating cellular trafficking, self-association and catalytic activity of essential proteins such as kinases and phosphatases. Because of their central role in cell signaling, cellular PDZ-containing proteins are preferential targets of viruses to hijack cellular function to their advantage. Here, we describe how the viral G protein of the rabies virus specifically targets the PDZ domain of neuronal enzymes during viral infection. By disrupting the complexes formed by cellular enzymes and their ligands, the virus triggers drastic effect on cell signaling and commitment of the cell to either survival (virulent strains) or death (vaccinal strains). We provide structural and biological evidences that the viral proteins act as competitors endowed with specificity and affinity in an essential cellular process by mimicking PDZ binding motif of cellular partners. Disruption of critical endogenous protein-protein interactions by viral protein drastically alters intracellular protein trafficking and catalytic activity of cellular proteins that control cell homeostasis. This work opens up many perspectives to mimic viral sequences and developing innovative therapies to manipulate cellular homeostasis.
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France.
Célia
C
Caillet-Saguy
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France.
Pierre
P
Maisonneuve
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France; Université Pierre et Marie Curie, Cellule Pasteur UPMC, rue du Docteur Roux, 75015 Paris, France.
Florent
F
Delhommel
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France.
Elouan
E
Terrien
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France.
Nicolas
N
Babault
Unité de Neuroimmunologie Virale, Département de Virologie, Institut Pasteur, Paris, France.
Monique
M
Lafon
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France.
Florence
F
Cordier
Unité de RMN des Biomolécules (CNRS UMR 3528), Département de Biologie Structurale et Chimie, Institut Pasteur, Paris, France. Electronic address: nicolas.wolff@pasteur.fr.
Nicolas
N
Wolff
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D054731:PDZ Domains; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000378:metabolism; D011820:Rabies virus / Q000378:metabolism / Q000502:physiology*
D017346:Protein Serine-Threonine Kinases; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4
Enzymatic regulation; Neuronal signaling; Neurons; PDZ domain; Phosphorylation; Rabies virus