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      Fusion of Enveloped Viruses in Endosomes

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          Abstract

          To initiate infection, enveloped viruses must fuse with a cell membrane, a process mediated by a dedicated viral fusion protein. To date, these proteins group into three basic structural classes. Most require priming (via a protease) to prepare them to respond to a fusion‐triggering signal. Known fusion triggers include receptors, low pH and proteases (and combinations thereof). Here, we provide an update on viral fusion protein priming and triggering, with a focus on virus fusion in endosomes.

          Abstract

          Ari Helenius launched the field of enveloped virus fusion in endosomes with a seminal paper in the Journal of Cell Biology in 1980. In the intervening years, a great deal has been learned about the structures and mechanisms of viral membrane fusion proteins as well as about the endosomes in which different enveloped viruses fuse and the endosomal cues that trigger fusion. We now recognize three classes of viral membrane fusion proteins based on structural criteria and four mechanisms of fusion triggering. After reviewing general features of viral membrane fusion proteins and viral fusion in endosomes, we delve into three characterized mechanisms for viral fusion triggering in endosomes: by low pH, by receptor binding plus low pH and by receptor binding plus the action of a protease. We end with a discussion of viruses that may employ novel endosomal fusion‐triggering mechanisms. A key take‐home message is that enveloped viruses that enter cells by fusing in endosomes traverse the endocytic pathway until they reach an endosome that has all of the environmental conditions ( pH, proteases, ions, intracellular receptors and lipid composition) to (if needed) prime and (in all cases) trigger the fusion protein and to support membrane fusion.

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          Most cited references 225

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          Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.

          Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.
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            Binding of hepatitis C virus to CD81.

            Chronic hepatitis C virus (HCV) infection occurs in about 3 percent of the world's population and is a major cause of liver disease. HCV infection is also associated with cryoglobulinemia, a B lymphocyte proliferative disorder. Virus tropism is controversial, and the mechanisms of cell entry remain unknown. The HCV envelope protein E2 binds human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Binding of E2 was mapped to the major extracellular loop of CD81. Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.
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              Virus entry by endocytosis.

              Although viruses are simple in structure and composition, their interactions with host cells are complex. Merely to gain entry, animal viruses make use of a repertoire of cellular processes that involve hundreds of cellular proteins. Although some viruses have the capacity to penetrate into the cytosol directly through the plasma membrane, most depend on endocytic uptake, vesicular transport through the cytoplasm, and delivery to endosomes and other intracellular organelles. The internalization may involve clathrin-mediated endocytosis (CME), macropinocytosis, caveolar/lipid raft-mediated endocytosis, or a variety of other still poorly characterized mechanisms. This review focuses on the cell biology of virus entry and the different strategies and endocytic mechanisms used by animal viruses.
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                Author and article information

                Journal
                Traffic
                Traffic
                10.1111/(ISSN)1600-0854
                TRA
                Traffic (Copenhagen, Denmark)
                John Wiley & Sons A/S (Former Munksgaard )
                1398-9219
                1600-0854
                07 April 2016
                June 2016
                : 17
                : 6 , Viruses, protein folding and endocytosis: a special issue dedicated to Ari Helenius ( doiID: 10.1111/tra.2016.17.issue-6 )
                : 593-614
                Affiliations
                [ 1 ] Department of Cell Biology University of Virginia Charlottesville VA USA
                [ 2 ] Department of Microbiology & Immunology Cornell University Ithaca NY USA
                Author notes
                [* ]Corresponding author: Judith M. White, jw7g@ 123456virginia.edu
                Article
                TRA12389
                10.1111/tra.12389
                4866878
                26935856
                20e8cba9-b8a3-4915-8615-4ae4ccca1f92
                © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                Page count
                Pages: 22
                Product
                Funding
                Funded by: NIH , open-funder-registry 10.13039/100000002;
                Award ID: R21 AI103601, RO1 AI114776, R21 AI111085, R21 AI117300
                Funded by: NSF , open-funder-registry 10.13039/100000001;
                Award ID: 1504846
                Funded by: National Institute of Allergy and Infectious Diseases , open-funder-registry 10.13039/100000060;
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Funded by: Department of Health and Human Services , open-funder-registry 10.13039/100000016;
                Award ID: HHSN272201400005C
                Funded by: Cornell Feline Health Center
                Funded by: Winn Feline Health Foundation
                Funded by: Morris Animal Foundation , open-funder-registry 10.13039/100001250;
                Categories
                Review
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                2.0
                June 2016
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

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