title: Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18.
abstract: Human CMV (HCMV)-encoded NK cell-evasion functions include an MHC class I homolog (UL18) with high affinity for the leukocyte inhibitory receptor-1 (CD85j, ILT2, or LILRB1) and a signal peptide (SP(UL40)) that acts by upregulating cell surface expression of HLA-E. Detailed characterization of SP(UL40) revealed that the N-terminal 14 aa residues bestowed TAP-independent upregulation of HLA-E, whereas C region sequences delayed processing of SP(UL40) by a signal peptide peptidase-type intramembrane protease. Most significantly, the consensus HLA-E-binding epitope within SP(UL40) was shown to promote cell surface expression of both HLA-E and gpUL18. UL40 was found to possess two transcription start sites, with utilization of the downstream site resulting in translation being initiated within the HLA-E-binding epitope (P2). Remarkably, this truncated SP(UL40) was functional and retained the capacity to upregulate gpUL18 but not HLA-E. Thus, our findings identify an elegant mechanism by which an HCMV signal peptide differentially regulates two distinct NK cell-evasion pathways. Moreover, we describe a natural SP(UL40) mutant that provides a clear example of an HCMV clinical virus with a defect in an NK cell-evasion function and exemplifies issues that confront the virus when adapting to immunogenetic diversity in the host.
authors.affiliation: School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Virginie
authors.initials: V
authors.lastname: Prod'homme
authors.forename: Peter
authors.initials: P
authors.lastname: Tomasec
authors.forename: Charles
authors.initials: C
authors.lastname: Cunningham
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Stanton
authors.forename: Brian P
authors.initials: BP
authors.lastname: McSharry
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Simone
authors.initials: S
authors.lastname: Cuff
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davison
authors.forename: Véronique M
authors.initials: VM
authors.lastname: Braud
authors.forename: Gavin W G
authors.initials: GW
authors.lastname: Wilkinson
mesh_terms: D000595:Amino Acid Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003586:Cytomegalovirus Infections; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000097625:HLA-E Antigens
chemical_list: D036022:Capsid Proteins; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; D000097625:HLA-E Antigens; C404228:UL40 glycoprotein, Cytomegalovirus; C079750:VP23 protein, Human herpesvirus 1