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Structural basis of vesicular stomatitis virus entry into host cells

Vesicular stomatitis virus (VSV) is an enveloped virus. Its membrane contains a unique glycoprotein (G) that plays a major role in the early stages of infection. First, it recognizes the receptors at the host cell surface and then, after endocytosis, it catalyzes the fusion of the viral and endosomal membranes, which allows the release of the viral nucleocapsid in the cytosol for the subsequent stages of the viral infection.
The LDL receptor (LDL-R) and other members of its family had been proposed to be VSV receptors. Researchers from the I2BC Virology Department and the SOLEIL synchrotron have just obtained two new structures of G in complex with two independent CR (for Cystein Rich) domains of the LDL-R (which contains seven CR domains in its ligand binding domain). Both CR domains occupy the same binding site on G. Two residues of G essential for the binding of CR domains were identified and their mutation abolishes the ability of G to bind its receptor without affecting its viral fusion properties. Remarkably, viruses pseudotyped with such G mutants are no longer infectious. This work shows that G has evolved to specifically recognize the CR domains encountered in members of the LDL-R family and that the only viral receptors belong to this family.
As VSV is an oncolytic virus and G is the most used glycoprotein for vectorization, this work opens many perspectives in medical biotechnology. Indeed, the possibility of decoupling the recognition of the receptor and the viral fusion properties makes it possible to envisage the construction of glycoproteins targeting other receptors. This might be used to pseudotype retroviruses or to construct VSVs fully retargeted to specific cells of interest.

Nikolic, J. * Belot, L.* et al. Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein. Nat Commun 9, 1029 (2018)

Aurélie Albertini
Yves Gaudin

par Communication - publié le