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

Prod'homme, Virginie, Tomasec, Peter, Cunningham, Charles, Lemberg, Marius K., Stanton, Richard James, McSharry, Brian, Wang, Edward Chung Yern, Cuff, Simone, Martoglio, Bruno, Davison, Andrew J., Braud, Veronique M. and Wilkinson, Gavin William Grahame 2012. Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18. The Journal of Immunology 188 (6) , pp. 2794-2804. 10.4049/jimmunol.1102068

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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 (SPUL40) that acts by upregulating cell surface expression of HLA-E. Detailed characterization of SPUL40 revealed that the N-terminal 14 aa residues bestowed TAP-independent upregulation of HLA-E, whereas C region sequences delayed processing of SPUL40 by a signal peptide peptidase-type intramembrane protease. Most significantly, the consensus HLA-E–binding epitope within SPUL40 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 SPUL40 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 SPUL40 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
Q Science > QR Microbiology > QR355 Virology
Additional Information: This work was supported by grants from the Wellcome Trust (WT090323MA), the United Kingdom Medical Research Council (G1000236), and the Biotechnology and Biological Sciences Research Council (BBF0098361).
Publisher: American Association of Immunologists
ISSN: 0022-1767
Funders: Wellcome Trust, United Kingdom Medical Research Council, Biotechnology and Biological Sciences Research Council
Last Modified: 28 Jun 2019 02:41
URI: http://orca.cf.ac.uk/id/eprint/37364

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