title: Expression of the RAE-1 family of stimulatory NK-cell ligands requires activation of the PI3K pathway during viral infection and transformation.
abstract: Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood. Here we show that murine cytomegalovirus (MCMV) infection activates the phosphatidylinositol-3-kinase (PI3K) pathway and that this activation is required for the induction of the RAE-1 family of mouse NKG2D ligands. Among the multiple PI3K catalytic subunits, inhibition of the p110α catalytic subunit blocks this induction. Similarly, inhibition of p110α PI3K reduces cell surface expression of RAE-1 on transformed cells. Many viruses manipulate the PI3K pathway, and tumors frequently mutate the p110α oncogene. Thus, our findings suggest that dysregulation of the PI3K pathway is an important signal to induce expression of RAE-1, and this may represent a commonality among various types of cellular stresses that result in the induction of NKG2D ligands.
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Tokuyama
authors.forename: Clarisse
authors.initials: C
authors.lastname: Lorin
authors.forename: Frederic
authors.initials: F
authors.lastname: Delebecque
authors.forename: Heiyoun
authors.initials: H
authors.lastname: Jung
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: Laurent
authors.initials: L
authors.lastname: Coscoy
mesh_terms: D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D058534:Class I Phosphatidylinositol 3-Kinases; D003586:Cytomegalovirus Infections / Q000503:physiopathology*; D005347:Fibroblasts / Q000821:virology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis*; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis*; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D055607:Receptors, Natural Killer Cell / Q000502:physiology*
chemical_list: C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D055607:Receptors, Natural Killer Cell; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase