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

Prod'homme, Virginie ORCID: https://orcid.org/0000-0002-9664-4710, Tomasec, Peter, Cunningham, Charles, Lemberg, Marius K., Stanton, Richard James ORCID: https://orcid.org/0000-0002-6799-1182, McSharry, Brian, Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, Cuff, Simone ORCID: https://orcid.org/0000-0002-0546-3579, Martoglio, Bruno, Davison, Andrew J., Braud, Veronique M. and Wilkinson, Gavin William Grahame ORCID: https://orcid.org/0000-0002-5623-0126 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:	06 Nov 2024 22:43
URI:	https://orca.cardiff.ac.uk/id/eprint/37364

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