Rubina, A. et al. (2023) ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways. Proceedings of the National Academy of Sciences of the United States of America, 120(33), e2303155120. (doi: 10.1073/pnas.2303155120) (PMID:37561786) (PMCID:PMC10438378)
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Abstract
Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defenses. In exploring the finding that HCMV infection up-regulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the pro-inflammatory antiviral cytokine TNFα, we found that the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype ‘sheddase’, a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b’ region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with an HCMV double-deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (P < 0.05) in an ADAM17-dependent fashion. These included reported substrates of ADAM17 with established immunological functions such as TNFR2 and jagged1, but also numerous unreported host and viral targets, such as nectin1, UL8, and UL144. Regulation of TNFα-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation.
| Item Type: | Articles |
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| Additional Information: | This work was funded by the Medical Research Council (MR/P001602/1 to P.T., G.W.G.W., and E.C.Y.W.; MR/V000489/1 to S.K., D.A.P., R.J.S., and E.C.Y.W.; MR/S00971X/1 to R.J.S. and E.C.Y.W.; MC_UU_12014/3 to A.J.D.) and further supported by two Cardiff University PhD Studentships (one part-funded by the Medical Research Council and one from the Systems Immunity University Research Institute). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). M.P.W. was supported by a Wellcome Trust Senior Clinical Research Fellowship (108070/Z/15/Z). An Attune flow cytometer (ThermoFisher) was used throughout which was obtained and serviced with the following grants: MR/P001602/1, MR/S00971X/1, MR/V000489/1, and Wellcome Trust grants 204870 (awarded to P Griffiths, UCL) and 207503/Z/17/Z (awarded to I Humphreys, Cardiff University). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Nichols, Mrs Jenna and Davison, Professor Andrew |
| Authors: | Rubina, A., Patel, M., Nightingale, K., Potts, M., Fielding, C. A., Kollnberger, S., Lau, B., Ladell, K., Miners, K. L., Nichols, J., Nobre, L., Roberts, D., Trinca, T. M., Twohig, J. P., Vlahava, V.-M., Davison, A. J., Price, D. A., Tomasec, P., Wilkinson, G. W. G., Weekes, M. P., Stanton, R. J., and Wang, E. C. Y. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Published Online: | 10 August 2023 |
| Copyright Holders: | Copyright © 2023 The Author(s). |
| First Published: | First published in PNAS 120(33):e2303155120 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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