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Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)

The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family o...

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Autores principales: Großkopf, Anna K., Schlagowski, Sarah, Fricke, Thomas, Ensser, Armin, Desrosiers, Ronald C., Hahn, Alexander S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959344/
https://www.ncbi.nlm.nih.gov/pubmed/33657166
http://dx.doi.org/10.1371/journal.ppat.1008979
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author Großkopf, Anna K.
Schlagowski, Sarah
Fricke, Thomas
Ensser, Armin
Desrosiers, Ronald C.
Hahn, Alexander S.
author_facet Großkopf, Anna K.
Schlagowski, Sarah
Fricke, Thomas
Ensser, Armin
Desrosiers, Ronald C.
Hahn, Alexander S.
author_sort Großkopf, Anna K.
collection PubMed
description The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by ~60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26–95 and 17577, Plxdc1 specifically interacts with RRV 26–95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26–95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV.
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spelling pubmed-79593442021-03-25 Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV) Großkopf, Anna K. Schlagowski, Sarah Fricke, Thomas Ensser, Armin Desrosiers, Ronald C. Hahn, Alexander S. PLoS Pathog Research Article The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by ~60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26–95 and 17577, Plxdc1 specifically interacts with RRV 26–95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26–95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV. Public Library of Science 2021-03-03 /pmc/articles/PMC7959344/ /pubmed/33657166 http://dx.doi.org/10.1371/journal.ppat.1008979 Text en © 2021 Großkopf et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Großkopf, Anna K.
Schlagowski, Sarah
Fricke, Thomas
Ensser, Armin
Desrosiers, Ronald C.
Hahn, Alexander S.
Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title_full Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title_fullStr Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title_full_unstemmed Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title_short Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
title_sort plxdc family members are novel receptors for the rhesus monkey rhadinovirus (rrv)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959344/
https://www.ncbi.nlm.nih.gov/pubmed/33657166
http://dx.doi.org/10.1371/journal.ppat.1008979
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