title: Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity.
abstract: Human cytomegalovirus (HCMV) encodes four 7-transmembrane-spanning (7TM) proteins, US28, US27, UL33, and UL78, which present important sequence homology with human chemokine receptors. Whereas US28 binds a large range of chemokines and disturbs host cell signaling at different levels, the others are orphans with largely unknown functions. Assembly of 2 different 7TM proteins into hetero-oligomeric complexes may profoundly change their respective functional properties. We show that HCMV-encoded UL33 and UL78 form heteromers with CCR5 and CXCR4 chemokine receptors in transfected human embryonic kidney 293T cells and monocytic THP-1 cells. Expression of UL33 and UL78 had pleiotropic, predominantly negative, effects on CCR5 and CXCR4 cell surface expression, ligand-induced internalization, signal transduction, and migration without modifying the chemokine binding properties of CCR5 and CXCR4. Importantly, the coreceptor activity of CCR5 and CXCR4 for HIV was largely impaired in the presence of UL33 and UL78 without affecting expression of the primary HIV entry receptor CD4 and its interaction with CCR5 and CXCR4. Collectively, we identified the first molecular function for the HCMV-encoded orphan UL33 and UL78 7TM proteins, namely the regulation of cellular chemokine receptors through receptor heteromerization.
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Tadagaki
authors.forename: Daniela
authors.initials: D
authors.lastname: Tudor
authors.forename: Florence
authors.initials: F
authors.lastname: Gbahou
authors.forename: Pia
authors.initials: P
authors.lastname: Tschische
authors.forename: Maria
authors.initials: M
authors.lastname: Waldhoer
authors.forename: Morgane
authors.initials: M
authors.lastname: Bomsel
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
mesh_terms: D002478:Cells, Cultured; D060085:Coinfection / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism / Q000821:virology; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism* / Q000502:physiology; D015728:Receptors, HIV / Q000378:metabolism* / Q000502:physiology; D014762:Viral Interference / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: C527276:CXCR4 protein, human; D008565:Membrane Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D015728:Receptors, HIV; C461643:UL33 protein, human cytomegalovirus; D014764:Viral Proteins