The hijacking of cellular machinery by pathogens, is essential to spread through the body of the host. Perturbation of signaling pathways that control cell homeostasis is a strategy developed by many other viruses upon infection. One originality of rabies virus is that it induces survival of infected neurons to ensure its propagation. The PDZ binding site (PDZ-BS) of the glycoprotein of rabies virus was identified as a key element to control survival and apoptosis pathways. The PDZ-BS of the glycoprotein from the virulent strain recognizes only two isoforms of the Microtubule Associated Serine/Threonine kinase family (MAST1 and MAST2). MAST2 acts as a survival inhibitor that stimulates neurite retraction and inhibits their elongation. In addition MAST2 interacts with the PDZ-BS of the phosphatase PTEN that is another inhibitor of neuronal survival. We propose that the glycoprotein disrupts the PTEN/MAST2 complex by competition with the PDZ-BS of PTEN and disturbs cellular homeostasis. The structure of the PDZ domain of MAST2 complexed with its endogenous ligand (PTEN13-Cter) reveals an original interaction with a large surface of interaction. This interaction network is preserved in MAST2 PDZ domain complexed with the viral ligand (Cyto13-vir). We demonstrated that the PDZ-BS of the glycoprotein is essential to trigger neuronal survival and that it induces a partial exclusion of PTEN from the nucleus. It is well established that the phosphorylation of PTEN is controlled by its phosphorylation state
