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

Virginie Prod'homme, Peter Tomasec, Charles Cunningham, Marius K. Lemberg, Richard J. Stanton, Brian P. McSharry, Eddie C.Y. Wang, Simone Cuff, Bruno Martoglio, Andrew J. Davison, Véronique M. Braud, Gavin W.G. Wilkinson

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2794-2804
Number of pages11
JournalJournal of Immunology
Volume188
Issue number6
DOIs
Publication statusPublished - 15 Mar 2012

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