Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling
In: PLoS Biology Plos Biology Plos Biology, 2021, 19 (9), pp.e3001392. ⟨10.1371/journal.pbio.3001392⟩, Jg. 19 (2021-06-14), Heft 9, p e3001392
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Zugriff:
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 H and L (gH/gL) binds with subnanomolar affinity to EphA2 via molecular mimicry of the receptor’s cellular ligands, ephrins (Eph family receptor interacting proteins), 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.
Herpesviruses are known to hijack cellular receptors to enter cells, but this study shows that human herpesvirus 8 takes this to another level by using its envelope glycoprotein complex gH/gL to mimic the EphA2 receptor’s natural ligands, ephrins.
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Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling
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Autor/in / Beteiligte Person: | Light, Taylor P. ; Hristova, Kalina ; Pederzoli, Riccardo ; Backovic, Marija ; Guardado-Calvo, Pablo ; Brun, Delphine ; Neipel, Frank ; Rey, Félix A. ; Haouz, Ahmed ; Johns Hopkins University (JHU) ; Virologie Structurale - Structural Virology ; Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) ; Cristallographie (Plateforme) - Crystallography (Platform) ; Universitätsklinikum Erlangen [Erlangen] ; This project has been supported via the recurrent funding from Institut Pasteur (MB, FR, PGC, RP, DB) and grants from NIH GM068619 and NSF MCB 1712740 (TL, KH). ; We thank Patrick Weber and Cédric Pissis the Crystallogenesis core facility at the Institut Pasteur for assistance with crystallization trials, and to the staff at the beamlines Proxima 1 and Proxima 2 at the French national synchrotron facility (SOLEIL, St Aubin, France) in particular to Leo Chavas and Bill Shepard for help with data collection and processing. We are grateful to Ignacio Fernandez and Jan Hellert for reading the manuscript and for their suggestions. ; This project has been supported via the recurrent funding from Institut Pasteur (FR), CNRS (FR) and ANR proposal #ANR-10-IHUB-0002 (FR), and grants from National Institute of Health GM068619 (KH) and National Science Foundation MCB 1712740 (KH). ; We thank Patrick Weber and Cédric Pissis, the Crystallogenesis core facility at the Institut Pasteur for assistance with crystallization trials, and to the staff at the beamlines Proxima 1 and Proxima 2 at the French national synchrotron facility (SOLEIL, St Aubin, France), in particular to Leo Chavas and Bill Shepard for help with data collection and processing. We are grateful to Ignacio Fernandez and Jan Hellert for reading the manuscript and for their suggestions. ; ANR-10-IBHU-0002,SLI,Institut Saint-Louis(2010) ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) |
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Zeitschrift: | PLoS Biology Plos Biology Plos Biology, 2021, 19 (9), pp.e3001392. ⟨10.1371/journal.pbio.3001392⟩, Jg. 19 (2021-06-14), Heft 9, p e3001392 |
Veröffentlichung: | HAL CCSD, 2021 |
Medientyp: | unknown |
ISSN: | 1545-7885 (print) ; 1544-9173 (print) |
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