title: A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: Trever T
authors.initials: TT
authors.lastname: Greene
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Tokuyama
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, United States.
authors.forename: Giselle M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, United States.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Greninger
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, United States.
authors.forename: Victor R
authors.initials: VR
authors.lastname: DeFilippis
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, United States.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, United States.
authors.forename: Laurent
authors.initials: L
authors.lastname: Coscoy
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D018146:Muromegalovirus / Q000502:physiology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D000099186:Histone Deacetylase 3; C527086:Klrk1 protein, mouse; C490521:Rae1 protein, mouse
keywords: CK2; NK cells; NKG2D; NKG2D ligands; herpesviruses; histone deacetylase; immunology; infectious disease; microbiology; mouse