title: Human cytomegalovirus UL7, a homologue of the SLAM-family receptor CD229, impairs cytokine production.
abstract: Human cytomegalovirus (HCMV), the β-herpesvirus prototype, has evolved a wide spectrum of mechanisms to counteract host immunity. Among them, HCMV uses cellular captured genes encoding molecules capable of interfering with the original host function or of fulfilling new immunomodulatory tasks. Here, we report on UL7, a novel HCMV heavily glycosylated transmembrane protein, containing an Ig-like domain that exhibits remarkable amino acid similarity to CD229, a cell-surface molecule of the signalling lymphocyte-activation molecule (SLAM) family involved in leukocyte activation. The UL7 Ig-like domain, which is well-preserved in all HCMV strains, structurally resembles the SLAM-family N-terminal Ig-variable domain responsible for the homophilic and heterophilic interactions that trigger signalling. UL7 is transcribed with early-late kinetics during the lytic infectious cycle. Using a mAb generated against the viral protein, we show that it is constitutively shed, through its mucine-like stalk, from the cell-surface. Production of soluble UL7 is enhanced by PMA and reduced by a broad-spectrum metalloproteinase inhibitor. Although UL7 does not hold the ability to interact with CD229 or other SLAM-family members, it shares with them the capacity to mediate adhesion to leukocytes, specifically to monocyte-derived DCs. Furthermore, we demonstrate that UL7 expression attenuates the production of proinflammatory cytokines TNF, IL-8 and IL-6 in DCs and myeloid cell lines. Thus, the ability of UL7 to interfere with cellular proinflammatory responses may contribute to viral persistence. These results enhance our understanding of those HCMV-encoded molecules involved in sustaining the balance between HCMV and the host immune system.
authors.affiliation: Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.forename: Natàlia
authors.initials: N
authors.lastname: Pérez-Carmona
authors.forename: M Mar
authors.initials: MM
authors.lastname: Albà
authors.forename: Kevin
authors.initials: K
authors.lastname: Robertson
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000737:chemistry; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D007155:Immunologic Factors; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007962:Leukocytes / Q000378:metabolism; D008213:Lymphocyte Activation; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D051379:Mice; D008969:Molecular Sequence Data; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D048069:Tumor Necrosis Factors / Q000096:biosynthesis; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D007155:Immunologic Factors; D015850:Interleukin-6; D016209:Interleukin-8; C430423:LY9 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D048069:Tumor Necrosis Factors; D014759:Viral Envelope Proteins; D014763:Viral Matrix Proteins; D045726:Metalloproteases; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase