Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry
Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (29), p.E3901-E3910 |
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| creator | Gianni, Tatiana Massaro, Raffaele Campadelli-Fiume, Gabriella |
| description | Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus—receptor-bound gD and gB—were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL. |
| doi_str_mv | 10.1073/pnas.1506846112 |
| format | Article |
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It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus—receptor-bound gD and gB—were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1506846112</identifier><identifier>PMID: 26157134</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino Acid Motifs ; Antibodies, Monoclonal - pharmacology ; Antibodies, Neutralizing - pharmacology ; Antigens, Neoplasm - chemistry ; Antigens, Neoplasm - metabolism ; Biological Sciences ; Brefeldin A - pharmacology ; Cell Adhesion Molecules - metabolism ; Cell Line, Tumor ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; dissociation ; Endocytosis - drug effects ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epithelial Cells - virology ; glycoproteins ; Herpes Simplex - metabolism ; Herpes Simplex - virology ; Herpesvirus 1, Human - drug effects ; Herpesvirus 1, Human - physiology ; Humans ; integrins ; Integrins - chemistry ; Integrins - metabolism ; Microscopy, Fluorescence ; Models, Biological ; Mutation - genetics ; Nectins ; PNAS Plus ; Protein Structure, Tertiary ; Proteolysis - drug effects ; receptors ; Solubility ; Viral Envelope Proteins - metabolism ; viral fusion proteins ; Virion - drug effects ; Virion - metabolism ; Virus Internalization - drug effects ; viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.E3901-E3910</ispartof><rights>Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3882-29172ea3f1fad01265d7640e303a427758b5baa4950274144d39127e5eb101393</citedby><cites>FETCH-LOGICAL-c3882-29172ea3f1fad01265d7640e303a427758b5baa4950274144d39127e5eb101393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/112/29.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26466143$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26466143$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26157134$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gianni, Tatiana</creatorcontrib><creatorcontrib>Massaro, Raffaele</creatorcontrib><creatorcontrib>Campadelli-Fiume, Gabriella</creatorcontrib><title>Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus—receptor-bound gD and gB—were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.</description><subject>Amino Acid Motifs</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Neutralizing - pharmacology</subject><subject>Antigens, Neoplasm - chemistry</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Biological Sciences</subject><subject>Brefeldin A - pharmacology</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>dissociation</subject><subject>Endocytosis - drug effects</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial Cells - virology</subject><subject>glycoproteins</subject><subject>Herpes Simplex - metabolism</subject><subject>Herpes Simplex - virology</subject><subject>Herpesvirus 1, Human - drug effects</subject><subject>Herpesvirus 1, Human - physiology</subject><subject>Humans</subject><subject>integrins</subject><subject>Integrins - chemistry</subject><subject>Integrins - metabolism</subject><subject>Microscopy, Fluorescence</subject><subject>Models, Biological</subject><subject>Mutation - genetics</subject><subject>Nectins</subject><subject>PNAS Plus</subject><subject>Protein Structure, Tertiary</subject><subject>Proteolysis - drug effects</subject><subject>receptors</subject><subject>Solubility</subject><subject>Viral Envelope Proteins - metabolism</subject><subject>viral fusion proteins</subject><subject>Virion - drug effects</subject><subject>Virion - metabolism</subject><subject>Virus Internalization - drug effects</subject><subject>viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9OGzEQh62qqKRpz5xAPvay4PF_XypVQEmlSBygvVreXW8wStapvYmUxyoPwjOxqw0pPfVkS_7mmxn_EDoBcg5EsYt16_I5CCI1lwD0HZoAMVBIbsh7NCGEqkJzyo_Rx5wfCSFGaPIBHVMJQgHjE1RdhZxjFVwXYotjg2d3v_BijpsUV3gxw-UOP__ZPj_JAsc0XnUR2s4vUmjxuqdi5_NAuqoL21Hj2hpvQ9pk7Nsu7T6ho8Yts_-8P6fo5_fr-8tZMb-9-XH5bV5UTGtaUAOKescaaFxNgEpRK8mJZ4Q5TpUSuhSlc9yIfi0OnNfMAFVe-BIIMMOm6OvoXW_Kla-roblb2nUKK5d2Nrpg_31pw4NdxK3lou_MdS_4shek-Hvjc2dXIVd-uXStj5tsQYPSVGnJ_49Ko5mhjJIevRjRKsWck28OEwGxQ4p2SNH-TbGvOHu7yIF_ja0H8B4YKg86oJYae81M_x1TdDoij7mL6Y2CSwmcsRexr64P</recordid><startdate>20150721</startdate><enddate>20150721</enddate><creator>Gianni, Tatiana</creator><creator>Massaro, Raffaele</creator><creator>Campadelli-Fiume, Gabriella</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20150721</creationdate><title>Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry</title><author>Gianni, Tatiana ; Massaro, Raffaele ; Campadelli-Fiume, Gabriella</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3882-29172ea3f1fad01265d7640e303a427758b5baa4950274144d39127e5eb101393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amino Acid Motifs</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibodies, Neutralizing - pharmacology</topic><topic>Antigens, Neoplasm - chemistry</topic><topic>Antigens, Neoplasm - metabolism</topic><topic>Biological Sciences</topic><topic>Brefeldin A - pharmacology</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>dissociation</topic><topic>Endocytosis - drug effects</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Epithelial Cells - virology</topic><topic>glycoproteins</topic><topic>Herpes Simplex - metabolism</topic><topic>Herpes Simplex - virology</topic><topic>Herpesvirus 1, Human - drug effects</topic><topic>Herpesvirus 1, Human - physiology</topic><topic>Humans</topic><topic>integrins</topic><topic>Integrins - chemistry</topic><topic>Integrins - metabolism</topic><topic>Microscopy, Fluorescence</topic><topic>Models, Biological</topic><topic>Mutation - genetics</topic><topic>Nectins</topic><topic>PNAS Plus</topic><topic>Protein Structure, Tertiary</topic><topic>Proteolysis - drug effects</topic><topic>receptors</topic><topic>Solubility</topic><topic>Viral Envelope Proteins - metabolism</topic><topic>viral fusion proteins</topic><topic>Virion - drug effects</topic><topic>Virion - metabolism</topic><topic>Virus Internalization - drug effects</topic><topic>viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gianni, Tatiana</creatorcontrib><creatorcontrib>Massaro, Raffaele</creatorcontrib><creatorcontrib>Campadelli-Fiume, Gabriella</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gianni, Tatiana</au><au>Massaro, Raffaele</au><au>Campadelli-Fiume, Gabriella</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2015-07-21</date><risdate>2015</risdate><volume>112</volume><issue>29</issue><spage>E3901</spage><epage>E3910</epage><pages>E3901-E3910</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus—receptor-bound gD and gB—were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>26157134</pmid><doi>10.1073/pnas.1506846112</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.E3901-E3910 |
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| subjects | Amino Acid Motifs Antibodies, Monoclonal - pharmacology Antibodies, Neutralizing - pharmacology Antigens, Neoplasm - chemistry Antigens, Neoplasm - metabolism Biological Sciences Brefeldin A - pharmacology Cell Adhesion Molecules - metabolism Cell Line, Tumor Cell Membrane - drug effects Cell Membrane - metabolism dissociation Endocytosis - drug effects Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial Cells - virology glycoproteins Herpes Simplex - metabolism Herpes Simplex - virology Herpesvirus 1, Human - drug effects Herpesvirus 1, Human - physiology Humans integrins Integrins - chemistry Integrins - metabolism Microscopy, Fluorescence Models, Biological Mutation - genetics Nectins PNAS Plus Protein Structure, Tertiary Proteolysis - drug effects receptors Solubility Viral Envelope Proteins - metabolism viral fusion proteins Virion - drug effects Virion - metabolism Virus Internalization - drug effects viruses |
| title | Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry |
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