The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

Cambridge Institute for Medical Research University of Cambridge Cambridge United Kingdom

Department of Cell Biology Harvard Medical School Boston United States

Division of Infection and Immunity School of Medicine Cardiff University Cardiff United Kingdom

Immunology Division Department of Pathology University of Cambridge Cambridge United Kingdom

MRC University of Glasgow Centre for Virus Research University of Glasgow Glasgow United Kingdom

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

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