Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18

J Immunol. 2012 Mar 15;188(6):2794-804. doi: 10.4049/jimmunol.1102068. Epub 2012 Feb 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Blotting, Northern
  • Blotting, Western
  • Capsid Proteins / genetics
  • Capsid Proteins / immunology
  • Capsid Proteins / metabolism*
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cell Separation
  • Cytomegalovirus / genetics
  • Cytomegalovirus / immunology
  • Cytomegalovirus / metabolism
  • Cytomegalovirus Infections
  • Flow Cytometry
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immune Evasion / immunology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Molecular Sequence Data
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Proteins / genetics
  • Viral Proteins / immunology
  • Viral Proteins / metabolism*

Substances

  • Capsid Proteins
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • UL40 glycoprotein, Cytomegalovirus
  • VP23 protein, Human herpesvirus 1
  • Viral Proteins