Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2013-05-01
|
| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00046-13 |
| _version_ | 1818683334300008448 |
|---|---|
| author | Doina Atanasiu Tina M. Cairns J. Charles Whitbeck Wan Ting Saw Samhita Rao Roselyn J. Eisenberg Gary H. Cohen |
| author_facet | Doina Atanasiu Tina M. Cairns J. Charles Whitbeck Wan Ting Saw Samhita Rao Roselyn J. Eisenberg Gary H. Cohen |
| author_sort | Doina Atanasiu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T10:33:05Z |
| format | Article |
| id | doaj.art-11718a2a284845c5b08b78366a1df839 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-17T10:33:05Z |
| publishDate | 2013-05-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-11718a2a284845c5b08b78366a1df8392022-12-21T21:52:27ZengAmerican Society for MicrobiologymBio2150-75112013-05-014210.1128/mBio.00046-13Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular ReceptorsDoina Atanasiu0Tina M. Cairns1J. Charles Whitbeck2Wan Ting Saw3Samhita Rao4Roselyn J. Eisenberg5Gary H. Cohen6Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.00046-13 |
| spellingShingle | Doina Atanasiu Tina M. Cairns J. Charles Whitbeck Wan Ting Saw Samhita Rao Roselyn J. Eisenberg Gary H. Cohen Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors mBio |
| title | Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors |
| title_full | Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors |
| title_fullStr | Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors |
| title_full_unstemmed | Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors |
| title_short | Regulation of Herpes Simplex Virus gB-Induced Cell-Cell Fusion by Mutant Forms of gH/gL in the Absence of gD and Cellular Receptors |
| title_sort | regulation of herpes simplex virus gb induced cell cell fusion by mutant forms of gh gl in the absence of gd and cellular receptors |
| url | https://journals.asm.org/doi/10.1128/mBio.00046-13 |
| work_keys_str_mv | AT doinaatanasiu regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT tinamcairns regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT jcharleswhitbeck regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT wantingsaw regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT samhitarao regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT roselynjeisenberg regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors AT garyhcohen regulationofherpessimplexvirusgbinducedcellcellfusionbymutantformsofghglintheabsenceofgdandcellularreceptors |