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

Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2303155120. doi: 10.1073/pnas.2303155120. Epub 2023 Aug 10.

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.

Keywords: ADAM17; Human cytomegalovirus; Immune regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism
  • Cell Membrane / metabolism
  • Cytokines / metabolism
  • Cytomegalovirus* / physiology
  • Humans
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Metalloproteases / metabolism
  • Proteome / metabolism
  • Proteomics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Tumor Necrosis Factor-alpha* / metabolism
  • Viral Proteins / metabolism

Substances

  • Tumor Necrosis Factor-alpha
  • Proteome
  • Receptors, Tumor Necrosis Factor, Type II
  • Membrane Proteins
  • Cytokines
  • Metalloproteases
  • ADAM17 Protein
  • UL144 ORF protein, Human herpesvirus 5
  • Membrane Glycoproteins
  • Viral Proteins
  • ADAM17 protein, human
  • UL148 protein, human cytomegalovirus