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ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways

Rubina, Anzelika, Patel, Mihil, Nightingale, Katie, Potts, Martin, Fielding, Ceri A. ORCID:, Kollnberger, Simon, Lau, Betty, Ladell, Kristin ORCID:, Miners, Kelly L., Nichols, Jenna, Nobre, Luis, Roberts, Dawn, Trinca, Terrence M., Twohig, Jason P., Vlahava, Virginia-Maria, Davison, Andrew J., Price, David A. ORCID:, Tomasec, Peter, Wilkinson, Gavin W. G., Weekes, Michael P., Stanton, Richard J. ORCID: and Wang, Eddie C. Y. ORCID: 2023. ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways. Proceedings of the National Academy of Sciences 120 (33) , e2303155120. 10.1073/pnas.2303155120

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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: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: National Academy of Sciences
ISSN: 0027-8424
Funders: MRC, Wellcome Trust
Date of First Compliant Deposit: 16 August 2023
Date of Acceptance: 23 June 2023
Last Modified: 11 Oct 2023 17:12

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