title: Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.
abstract: Human cytomegalovirus encodes at least 25 membrane glycoproteins that are found in the viral envelope(1). While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, and the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells(2-5). Two reports suggested that gB binds to ErbB1 and PDGFRα (refs 6,7); however, these results do not explain the tropism of the virus and were recently challenged(8,9). Here, we provide a 19 Å reconstruction for the gHgLgO trimer and show that it binds with high affinity through the gO subunit to PDGFRα, which is expressed on fibroblasts but not on epithelial cells. We also provide evidence that the trimer is essential for viral entry in both fibroblasts and epithelial cells. Furthermore, we identify the pentamer, which is essential for infection of epithelial cells, as a trigger for the ErbB pathway. These findings help explain the broad tropism of human cytomegalovirus and indicate that PDGFRα and the viral gO subunit could be targeted by novel anti-viral therapies.
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Anna
authors: A
authors: Kabanova
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Jessica
authors: J
authors: Marcandalli
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Tongqing
authors: T
authors: Zhou
authors: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors: Siro
authors: S
authors: Bianchi
authors: Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors: Ulrich
authors: U
authors: Baxa
authors: Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors: Yaroslav
authors: Y
authors: Tsybovsky
authors: Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
authors: Daniele
authors: D
authors: Lilleri
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Chiara
authors: C
authors: Silacci-Fregni
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Mathilde
authors: 0000-0001-7538-4262
authors: M
authors: Foglierini
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Blanca Maria
authors: BM
authors: Fernandez-Rodriguez
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Aliaksandr
authors: A
authors: Druz
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Baoshan
authors: B
authors: Zhang
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.|Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors: Roger
authors: R
authors: Geiger
authors: Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.
authors: Massimiliano
authors: M
authors: Pagani
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Federica
authors: F
authors: Sallusto
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Peter D
authors: PD
authors: Kwong
authors: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors: Davide
authors: 0000-0002-5797-1364
authors: D
authors: Corti
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.|Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors: Antonio
authors: A
authors: Lanzavecchia
authors: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors: Laurent
authors: 0000-0002-8860-7928
authors: L
authors: Perez
mesh_terms: D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008854:Microscopy, Electron; D011485:Protein Binding; D011487:Protein Conformation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D011991:Receptors, Virus; C077406:UL115 protein, Human herpesvirus 5; D014759:Viral Envelope Proteins; C071440:glycoprotein H, Cytomegalovirus; C439068:glycoprotein O, cytomegalovirus; D020796:Receptor, Platelet-Derived Growth Factor alpha