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Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

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posted on 01.04.2022, 14:53 by Ceri A. Fielding, Rebecca Aicheler, Richard J. Stanton, Eddie C. Y. Wang, Song Han, Sepehr Seirafian, James Davies, Brian P. McSharry, Michael P. Weekes, P. Robin Antrobus, Virginie Prod'homme, Fabien P. Blanchet, Daniel Sugrue, Simone Cuff, Dawn Roberts, Andrew J. Davison, Paul J. Lehner, Gavin W. G. Wilkinson, Peter Tomasec
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.

Funding

This study was funded by the Medical Research Council (Grant no. G1000236, http://www.mrc.ac.uk/index.htm) and the Wellcome Trust (Grant no. WT090323MA, http://www.wellcome.ac.uk/). MPW is supported by a Postdoctoral Fellowship for MB/PhD graduates from the Wellcome Trust (093966/Z/10/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Published in

PLOS Pathogens

Publisher

Public Library of Science

Version

VoR (Version of Record)

Citation

Fielding, C.A., Aicheler, R., Stanton, R.J., Wang, E.C., Han, S., Seirafian, S., Davies, J., McSharry, B.P., Weekes, M.P., Antrobus, P.R., Prod'homme, V., Blanchet, F.P., Sugrue, D., Cuff, S., Roberts, D., Davison, A.J., Lehner, P.J., Wilkinson, G.W. & Tomasec, P. (2014) 'Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation', PLoS Pathogens, 10(5), p.e1004058.

Print ISSN

1553-7366

Electronic ISSN

1553-7374

Cardiff Met Affiliation

Cardiff School of Sport and Health Sciences

Cardiff Met Authors

Rebecca Aicheler

Cardiff Met Research Centre/Group

  • Microbiology & Infection

Copyright Holder

© The Authors

Language

en

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