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

• DOI: 10.1073/pnas.2303155120
• Publication Date: 2023-08-10T17:47:24Z
• Authors: Anzelika Rubina; Mihil Patel; Katie Nightingale; Martin Potts; Ceri A. Fielding; Simon Kollnberger; Betty Lau; Kristin Ladell; Kelly L. Miners; Jenna Nichols; Luis Nobre; Dawn Roberts; Terrence M. Trinca; Jason P. Twohig; Virginia-Maria Vl...; Andrew J. Davison; David A. Price; Peter Tomasec; Gavin W. G. Wilki...; Michael P. Weekes; Richard J. Stanton; Eddie C. Y. Wang
• Keywords: Immunological synapse; Jurkat cells

Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence 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), ligand for pro-inflammatory antiviral cytokine TNFα, we found underlying mechanism was due targeting of protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 prototype 'sheddase', family proteases cleaves other membrane-bound proteins release biologically active ectodomains into supernatant. impaired surface expression through action two virally-encoded in UL/b' region, UL148 and UL148D. Proteomic plasma membrane profiling cells infected with an double-deletion mutant UL148D restored expression, combined functional blockade, showed stabilized 114 (P < 0.05) ADAM17-dependent fashion. These included reported substrates established immunological functions such as TNFR2 jagged1, but also numerous unreported viral targets, nectin1, UL8, UL144. Regulation TNFα-induced responses NK inhibition during were dependent on this impairment ADAM17. We therefore identify immunoregulatory which single sheddase enables broad regulation multiple critical receptors, revealing paradigm viral-encoded immunomodulation.