Selective induction of expression of a ligand for the NKG2D receptor by proteasome inhibitors.
The interaction of the activating receptor NKG2D with its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but dysregulation of this system may lead to autoimmunity. The expression of NKG2D ligands is induced by cellular "stress." However, the regulation of expression of these molecules is not well understood. Here, we show that cells treated with proteasome inhibitors can become more susceptible to cytotoxicity mediated by natural killer cells because of the induction of expression of ligands for NKG2D, specifically ULBP2, but not down-regulation of MHC class I. Treatment with proteasome inhibitors led to up-regulation of ULBP2 expression in multiple, but not all, cell lines tested. This increase in expression of ULBP2 at the cell surface correlated with induction of transcription of the ULBP2 gene and synthesis of ULBP2 protein. In contrast, treatment with inhibitors of histone deacetylases led to increased levels of mRNA and protein, for both ULBP2 and MHC class I-related chain A/B molecules. Thus, different types of stress can trigger up-regulated expression of different sets of NKG2D ligands. Proteasome inhibitors are proving to be of significant value in the treatment of hematologic malignancies and these observations may help to better understand the biology of therapy with these compounds.
Valés-Gómez
Mar
M
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Chisholm
Susan E
SE
Cassady-Cain
Robin L
RL
Roda-Navarro
Pedro
P
Reyburn
Hugh T
HT
D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005347:Fibroblasts / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell
D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423230:ULBP2 protein, human; D046988:Proteasome Endopeptidase Complex