A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repressionTrever T Greene, Maria Tokuyama, Giselle M Knudsen, Michele Kunz, James Lin, Alexander L Greninger, Victor R DeFilippis, Joseph L DeRisi, David H Raulet, Laurent Coscoy
eLIFE, 2016Abstract: Natural Killer (NK) cells are essential for control of viral infection and cancer. NK cells
express NKG2D, an activating receptor that directly recognizes NKG2D ligands. These are
expressed at low level on healthy cells, but are induced by stresses like infection and
transformation. The physiological events that drive NKG2D ligand expression during infection are
still poorly understood. We observed that the mouse cytomegalovirus encoded protein m18 is
necessary and sufficient to drive expression of the RAE-1 family of NKG2D ligands. We
demonstrate that RAE-1 is transcriptionally repressed by histone deacetylase inhibitor 3 (HDAC3) in
healthy cells, and m18 relieves this repression by directly interacting with Casein Kinase II and
preventing it from activating HDAC3. Accordingly, we found that HDAC inhibiting proteins from
human herpesviruses induce human NKG2D ligand ULBP-1. Thus our findings indicate that virally
mediated HDAC inhibition can act as a signal for the host to activate NK-cell recognition.
