Journal
MOLECULAR IMMUNOLOGY
Volume 53, Issue 3, Pages 255-264Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2012.08.011
Keywords
NKG2D-ligand; ULBP2; Calcium; Galectin-1; HDAC-inhibitor; Cancer
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Funding
- Novo Nordisk Foundation
- Mogens Svarre Mogensens Fond
- Frimodt-Heineke-Fonden
- Ekspeditionssekretaer, cand.jur. Torkil Steenbecks legat
- Grosserer L.F. Foghts Fond
- Beckett-Fonden
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In this study we demonstrate that histone deacetylase (HDAC)-inhibitor mediated cell surface expression of the structural different NKG2D-ligands MICA/B and ULBP2 is calcium-dependent. Treatment with the calcium chelator EGTA inhibited constitutive as well as HDAC-inhibitor induced MICA/B and ULBP2 cell surface expression on melanoma cells and Jurkat T-cells. A NKG2D-dependent cytolytic assay and staining with a recombinant NKG2D-Fc fusion protein showed that calcium chelation impaired the functional ability of NKG2D-ligands induced by HDAC-inhibitor treatment. The HDAC-inhibitor induced cell surface expression of ULBP2, but not MICA/B, was sensitive to treatment calmidazolium and trifluoperazine, two agents known to block calcium signaling. siRNA-mediated knock-down of the calcium-regulated proteins calmodulin or calpain did however not affect NKG2D-ligand cell surface expression on Jurkat T-cells. We further show that secretion and cell surface binding of the calcium-regulating protein galectin-1 is enhanced upon HDAC-inhibitor treatment of melanoma cells. However, binding of galectin-1 to cell surface glycoproteins was not critical for constitutive or HDAC-inhibitor induced MICA/B and ULBP2 cell surface expression. We provide evidence that MICA/B and ULBP2 cell surface expression is controlled differently by calcium, which adds to the increasing perception that cell surface expression of MICA/B and ULBP2 is controlled by distinct signal transduction pathways. (C) 2012 Elsevier Ltd. All rights reserved.
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