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  • br Acknowledgements This work was supported by the National

    2022-08-05


    Acknowledgements This work was supported by the National Key Research and Development Program of China [2017YFD0400106]; Innovation of modern Project[F18R02-03].
    Introduction The Vesiculovirus genus is one of the six genera of the rhabdovirus family. The prototype vesiculovirus is vesicular stomatitis virus (VSV). It is an arbovirus that can infect insects, cattle, horses and pigs. In mammals, its ability to preferentially infect and kill tumor cells makes it a promising oncolytic virus for the treatment of cancer [1], [2], [3]. Although VSV-associated disease is generally benign, other vesiculoviruses can be deadly to humans. This is the case for the Chandipura virus (CHAV), which is an emerging human pathogen associated with deadly encephalitis, principally affecting children in the tropical areas of India and which has, in recent years, caused several outbreaks with high mortality rates [4]. As all rhabdoviruses, vesiculoviruses are enveloped viruses having a rigid bullet shape with a flat base and a round tip. Their genome encodes five structural proteins including a single transmembrane glycoprotein (G). G is a type I membrane glycoprotein. After cleavage of the amino-terminal signal peptide, the mature glycoprotein is about 500 IRAK inhibitor 6 long (495 for VSV G). The bulk of the mass of G is located outside the viral membrane and constitutes the amino-terminal ectodomain. G is anchored in the membrane by a single α-helical transmembrane segment. The small intraviral domain is probably involved in interactions with internal proteins. G plays a critical role during the initial steps of virus infection [5]. First, it is responsible for virus attachment to specific receptors, which, in the case of VSV G, are the members of the low-density lipoprotein receptor family [6], [7]. After binding, virions enter the cell by a clathrin-mediated endocytic pathway [8], [9]. In the acidic environment of the endocytic vesicle, G triggers the fusion between the viral and endosomal membranes, which releases the genome in the cytosol for the subsequent steps of infection [5]. Fusion is catalyzed by a low-pH-induced large structural transition from a pre- to a post-fusion conformation which are both trimeric [10]. Remarkably, for rhabdoviruses, the structural transition is reversible [11], [12], [13], [14], and in fact, there is an equilibrium between different states of G, which is shifted toward the trimeric post-fusion conformation at low pH [5], [15]. VSV G structure reveals an organization distinct from both class I fusion glycoproteins, such as the influenza virus hemagglutinin (HA) and the paramyxovirus fusion protein (F), and class II fusion glycoproteins of several positive strand RNA viruses, such as the E protein of flaviviruses and E1 of alphaviruses, and of the bunyaviridae family [16]. In fact, together with baculovirus gp64 [17], herpesviruses gB [18], [19], [20], [21] and thogotovirus Gp [22], rhabdovirus G defines the class III of fusion proteins [23]. VSV G is the only member of this class for which high-resolution structures of both the pre- and post-fusion states are available [24], [25]. Low-resolution electron microscopy (EM) structures of the putative pre-fusion state of HSV1 gB have been obtained [26], [27], but those structures have led to opposite interpretations concerning the orientation of the fusion domains (FDs) either pointing away or toward the anchoring membrane. Nevertheless, the localization of monoclonal antibodies binding sites [26] and spectroscopic characterization of functional fluorescent gB [28] are consistent with a model of pre-fusion gB similar to the pre-fusion VSV G crystal structure [25] (i.e., with the fusion loops pointing toward the anchoring membrane). Similar to other class III proteins, the polypeptide chain of the G ectodomain folds into three distinct domains termed the FD, the pleckstrin homology domain (PHD) and the trimerization domain (TrD) [23] (Fig. 1). The FD is an extended β-sheet structure at the tip of which are located the two hydrophobic fusion loops that interact with the target membrane to initiate the fusion process. This organization of the class III FD is reminiscent of that of class II fusion proteins. The TrD comprises an α-helix involved in the trimerization of the glycoprotein and a β-sheet-rich region connected to the C-terminal segment of the ectodomain.