title: The selenium metabolite methylselenol regulates the expression of ligands that trigger immune activation through the lymphocyte receptor NKG2D.
abstract: For decades, selenium research has been focused on the identification of active metabolites, which are crucial for selenium chemoprevention of cancer. In this context, the metabolite methylselenol (CH3SeH) is known for its action to selectively kill transformed cells through mechanisms that include increased formation of reactive oxygen species, induction of DNA damage, triggering of apoptosis, and inhibition of angiogenesis. Here we reveal that CH3SeH modulates the cell surface expression of NKG2D ligands. The expression of NKG2D ligands is induced by stress-associated pathways that occur early during malignant transformation and enable the recognition and elimination of tumors by activating the lymphocyte receptor NKG2D. CH3SeH regulated NKG2D ligands both on the transcriptional and the posttranscriptional levels. CH3SeH induced the transcription of MHC class I polypeptide-related sequence MICA/B and ULBP2 mRNA. However, the induction of cell surface expression was restricted to the ligands MICA/B. Remarkably, our studies showed that CH3SeH inhibited ULBP2 surface transport through inhibition of the autophagic transport pathway. Finally, we identified extracellular calcium as being essential for CH3SeH regulation of NKG2D ligands. A balanced cell surface expression of NKG2D ligands is considered to be an innate barrier against tumor development. Therefore, our work indicates that the application of selenium compounds that are metabolized to CH3SeH could improve NKG2D-based immune therapy.
authors.affiliation: From the Laboratory of Immunology, Department of Veterinary Disease Biology.
authors.forename: Michael
authors.initials: M
authors.lastname: Hagemann-Jensen
authors.affiliation: From the Laboratory of Immunology, Department of Veterinary Disease Biology.
authors.forename: Franziska
authors.initials: F
authors.lastname: Uhlenbrock
authors.affiliation: From the Laboratory of Immunology, Department of Veterinary Disease Biology.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kehlet
authors.affiliation: From the Laboratory of Immunology, Department of Veterinary Disease Biology.
authors.forename: Lars
authors.initials: L
authors.lastname: Andresen
authors.affiliation: Department of Pharmacy, and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gabel-Jensen
authors.affiliation: Department of Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Ellgaard
authors.affiliation: Department of Pharmacy, and.
authors.forename: Bente
authors.initials: B
authors.lastname: Gammelgaard
authors.affiliation: From the Laboratory of Immunology, Department of Veterinary Disease Biology, sosk@sund.ku.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
mesh_terms: D001343:Autophagy; D002118:Calcium / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000378:metabolism; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology*; D013058:Mass Spectrometry; D000432:Methanol / Q000031:analogs & derivatives* / Q000737:chemistry; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000737:chemistry*; D012323:RNA Processing, Post-Transcriptional; D012643:Selenium / Q000737:chemistry*
chemical_list: D056572:Histone Deacetylase Inhibitors; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016566:Organoselenium Compounds; C019003:methaneselenol; D012643:Selenium; D002118:Calcium; D000432:Methanol
keywords: Autophagy; Molecular Cell Biology; Natural Killer Cells (NK cells); Selenium; Trafficking; Tumor Immunology