43
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          Herpesvirus entry requires the viral glycoprotein triad of gB and gH/gL to carry out fusion between the virion envelope and a cellular membrane in order to release the nucleocapsid into the target cell. Herpes simplex virus (HSV) also requires glycoprotein gD to initiate the fusion cascade by binding a cell receptor such as nectin 1 or herpesvirus entry mediator (HVEM). While the structure of gB is that of a class III fusion protein, gH/gL has no features that resemble other viral fusion proteins. Instead, it is suggested that gH/gL acts as a regulator of gB. The crystal structure of HSV-2 gH/gL was obtained with a functional protein that had a deletion of 28 residues at the gH N terminus (gHΔ48/gL). Unexplainably, monoclonal antibodies (MAbs) with virus-neutralizing activity map to these residues. To reconcile these two disparate observations, we studied the ability of gHΔ48/gL to regulate fusion. Here, we show that the protein induces low (constitutive) levels of fusion by gB in the absence of gD and/or receptor. However, when gD and receptor are present, this mutant functions as well as does wild-type (wt) gH/gL for fusion. We propose that gHΔ48/gL has an intermediate structure on the pathway leading to full regulatory activation. We suggest that a key step in the pathway of fusion is the conversion of gH/gL to an activated state by receptor-bound gD; this activated gH/gL resembles gHΔ48/gL.

          IMPORTANCE

          Herpes simplex viruses (HSVs) cause many human diseases, from mild cold sores to lethal neonatal herpes. As an enveloped virus, HSV must fuse its membrane with a host membrane in order for replication to take place. The virus uses four glycoproteins for this process, gD, gB, and gH/gL, and either of two cell receptors, herpesvirus entry mediator (HVEM) and nectin 1. Although the virus can enter the cell by direct fusion at the plasma membrane or via endocytosis, the same four glycoproteins are involved. The absence of any of these proteins abolishes the entry process. Here, we show that a mutant form of gH/gL, gHΔ48/gL, can induce fusion of gB-expressing cells in the absence of gD and a gD receptor. Our study supports the concept that gB is the HSV fusogen and its activity is regulated by gH/gL.

          Related collections

          Most cited references48

          • Record: found
          • Abstract: found
          • Article: not found

          Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme.

          Recent work has identified three distinct classes of viral membrane fusion proteins based on structural criteria. In addition, there are at least four distinct mechanisms by which viral fusion proteins can be triggered to undergo fusion-inducing conformational changes. Viral fusion proteins also contain different types of fusion peptides and vary in their reliance on accessory proteins. These differing features combine to yield a rich diversity of fusion proteins. Yet despite this staggering diversity, all characterized viral fusion proteins convert from a fusion-competent state (dimers or trimers, depending on the class) to a membrane-embedded homotrimeric prehairpin, and then to a trimer-of-hairpins that brings the fusion peptide, attached to the target membrane, and the transmembrane domain, attached to the viral membrane, into close proximity thereby facilitating the union of viral and target membranes. During these conformational conversions, the fusion proteins induce membranes to progress through stages of close apposition, hemifusion, and then the formation of small, and finally large, fusion pores. Clearly, highly divergent proteins have converged on the same overall strategy to mediate fusion, an essential step in the life cycle of every enveloped virus.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Fusing structure and function: a structural view of the herpesvirus entry machinery.

            Herpesviruses are double-stranded DNA, enveloped viruses that infect host cells through fusion with either the host cell plasma membrane or endocytic vesicle membranes. Efficient infection of host cells by herpesviruses is remarkably more complex than infection by other viruses, as it requires the concerted effort of multiple glycoproteins and involves multiple host receptors. The structures of the major viral glycoproteins and a number of host receptors involved in the entry of the prototypical herpesviruses, the herpes simplex viruses (HSVs) and Epstein-Barr virus (EBV), are now known. These structural studies have accelerated our understanding of HSV and EBV binding and fusion by revealing the conformational changes that occur on virus-receptor binding, depicting potential sites of functional protein and lipid interactions, and identifying the probable viral fusogen.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Crystal structure of glycoprotein B from herpes simplex virus 1.

              Glycoprotein B (gB) is the most conserved component of the complex cell-entry machinery of herpes viruses. A crystal structure of the gB ectodomain from herpes simplex virus type 1 reveals a multidomain trimer with unexpected homology to glycoprotein G from vesicular stomatitis virus (VSV G). An alpha-helical coiled-coil core relates gB to class I viral membrane fusion glycoproteins; two extended beta hairpins with hydrophobic tips, homologous to fusion peptides in VSV G, relate gB to class II fusion proteins. Members of both classes accomplish fusion through a large-scale conformational change, triggered by a signal from a receptor-binding component. The domain connectivity within a gB monomer would permit such a rearrangement, including long-range translocations linked to viral and cellular membranes.
                Bookmark

                Author and article information

                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society of Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                26 February 2013
                Mar-Apr 2013
                : 4
                : 2
                : e00046-13
                Affiliations
                Department of Microbiology, School of Dental Medicine, [ a ] and
                Department of Pathobiology, School of Veterinary Medicine, [ b ] University of Pennsylvania, Philadelphia, Pennsylvania, USA
                Author notes
                Address correspondence to Gary H. Cohen, ghc@ 123456dental.upenn.edu .

                Editor Terence Dermody, Vanderbilt University School of Medicine

                Article
                mBio00046-13
                10.1128/mBio.00046-13
                3585445
                23443004
                531bb15e-7976-4a8c-83b4-9ff99f626704
                Copyright © 2013 Atanasiu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 January 2013
                : 24 January 2013
                Page count
                Pages: 9
                Categories
                Research Article
                Custom metadata
                March/April 2013

                Life sciences
                Life sciences

                Comments

                Comment on this article