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Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling

View ORCID ProfileTaylor P. Light, Delphine Brun, View ORCID ProfilePablo Guardado-Calvo, View ORCID ProfileRiccardo Pederzoli, View ORCID ProfileAhmed Haouz, Frank Neipel, View ORCID ProfileFelix Rey, View ORCID ProfileKalina Hristova, View ORCID ProfileMarija Backovic
doi: https://doi.org/10.1101/2021.03.26.437132
Taylor P. Light
1Department of Materials Science and Engineering and Institute for NanoBioTechnology, John Hopkins University, Baltimore, Maryland, USA
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Delphine Brun
2Unité de Virologie Structurale, Institut Pasteur, Département de Virologie, 28 rue du Dr Roux, 75015 Paris, France; CNRS, UMR3569, Paris, France
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Pablo Guardado-Calvo
2Unité de Virologie Structurale, Institut Pasteur, Département de Virologie, 28 rue du Dr Roux, 75015 Paris, France; CNRS, UMR3569, Paris, France
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Riccardo Pederzoli
2Unité de Virologie Structurale, Institut Pasteur, Département de Virologie, 28 rue du Dr Roux, 75015 Paris, France; CNRS, UMR3569, Paris, France
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Ahmed Haouz
3Crystallography Platform C2RT, Institut Pasteur, 25 rue du Dr. Roux, Paris 75015, Paris, France; CNRS UMR 3528
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Frank Neipel
4Virologisches Institut, Universitaetsklinikum Erlangen, Schlossgarten 4, D-91054 Erlangen, Germany
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Felix Rey
2Unité de Virologie Structurale, Institut Pasteur, Département de Virologie, 28 rue du Dr Roux, 75015 Paris, France; CNRS, UMR3569, Paris, France
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Kalina Hristova
1Department of Materials Science and Engineering and Institute for NanoBioTechnology, John Hopkins University, Baltimore, Maryland, USA
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  • For correspondence: marija@pasteur.fr
Marija Backovic
2Unité de Virologie Structurale, Institut Pasteur, Département de Virologie, 28 rue du Dr Roux, 75015 Paris, France; CNRS, UMR3569, Paris, France
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  • For correspondence: marija@pasteur.fr
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ABSTRACT

Human herpesvirus 8 (HHV-8) is an oncogenic virus that enters cells by fusion of the viral and endosomal cellular membranes in a process mediated by viral surface glycoproteins. One of the cellular receptors hijacked by HHV-8 to gain access to cells is the EphA2 tyrosine kinase receptor, and the mechanistic basis of EphA2-mediated viral entry remains unclear. Using X-ray structure analysis, targeted mutagenesis and binding studies, we here show that the HHV-8 envelope glycoprotein complex gH/gL binds with sub-nanomolar affinity to EphA2 via molecular mimicry of the receptor’s cellular ligands, ephrins, revealing a pivotal role for the conserved gH residue E52 and the amino-terminal peptide of gL. Using FSI-FRET and cell contraction assays, we further demonstrate that the gH/gL complex also functionally mimics ephrin ligand by inducing EphA2 receptor association via its dimerization interface, thus triggering receptor signaling for cytoskeleton remodeling. These results now provide novel insight into the entry mechanism of HHV-8, opening avenues for the search of therapeutic agents that could interfere with HHV-8 related diseases.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.rcsb.org/structure/7b7n

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Posted March 28, 2021.
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Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling
Taylor P. Light, Delphine Brun, Pablo Guardado-Calvo, Riccardo Pederzoli, Ahmed Haouz, Frank Neipel, Felix Rey, Kalina Hristova, Marija Backovic
bioRxiv 2021.03.26.437132; doi: https://doi.org/10.1101/2021.03.26.437132
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Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling
Taylor P. Light, Delphine Brun, Pablo Guardado-Calvo, Riccardo Pederzoli, Ahmed Haouz, Frank Neipel, Felix Rey, Kalina Hristova, Marija Backovic
bioRxiv 2021.03.26.437132; doi: https://doi.org/10.1101/2021.03.26.437132

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