Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells
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Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells. / Møller, Sofie H; Mellergaard, Maiken; Madsen, Mikkel; Bermejo, Amaia V; Jepsen, Stine D; Hansen, Marie H; Høgh, Rikke I; Aldana, Blanca Irene; Desler, Claus; Rasmussen, Lene Juel; Sustarsic, Elahu G; Gerhart-Hines, Zachary; Daskalaki, Evangelia; Wheelock, Craig E; Hiron, Thomas K; Lin, Da; O'Callaghan, Christopher A; Wandall, Hans H; Andresen, Lars; Skov, Søren.
In: Frontiers in Immunology, Vol. 11, 1968, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells
AU - Møller, Sofie H
AU - Mellergaard, Maiken
AU - Madsen, Mikkel
AU - Bermejo, Amaia V
AU - Jepsen, Stine D
AU - Hansen, Marie H
AU - Høgh, Rikke I
AU - Aldana, Blanca Irene
AU - Desler, Claus
AU - Rasmussen, Lene Juel
AU - Sustarsic, Elahu G
AU - Gerhart-Hines, Zachary
AU - Daskalaki, Evangelia
AU - Wheelock, Craig E
AU - Hiron, Thomas K
AU - Lin, Da
AU - O'Callaghan, Christopher A
AU - Wandall, Hans H
AU - Andresen, Lars
AU - Skov, Søren
N1 - Copyright © 2020 Møller, Mellergaard, Madsen, Bermejo, Jepsen, Hansen, Høgh, Aldana, Desler, Rasmussen, Sustarsic, Gerhart-Hines, Daskalaki, Wheelock, Hiron, Lin, O’Callaghan, Wandall, Andresen and Skov.
PY - 2020
Y1 - 2020
N2 - Immune surveillance of cancer cells is facilitated by the Natural Killer Group 2D (NKG2D) receptor expressed by different lymphocyte subsets. It recognizes NKG2D ligands that are rarely expressed on healthy cells, but upregulated by tumorigenesis, presenting a target for immunological clearance. The molecular mechanisms responsible for NKG2D ligand regulation remain complex. Here we report that cancer cell metabolism supports constitutive surface expression of the NKG2D ligand MHC class I chain-related proteins A (MICA). Knockout of the N-glycosylation gene N-acetylglucosaminyltransferase V (MGAT5) in HEK293 cells induced altered metabolism and continuous high MICA surface expression. MGAT5 knockout cells were used to examine the association of cell metabolism and MICA expression through genetic, pharmacological and metabolic assays. Findings were verified in cancer cell lines. Cells with constitutive high MICA expression showed enhanced spare respiratory capacity and elevated mitochondrial efflux of citrate, determined by extracellular flux analysis and metabolomics. MICA expression was reduced by inhibitors of mitochondrial function, FCCP and etomoxir e.g., and depended on conversion of citrate to acetyl-CoA and oxaloacetate by ATP citrate lyase, which was also observed in several cancer cell types. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis revealed that upregulated MICA transcription was associated with an open chromatin structure at the MICA transcription start site. We identify mitochondria and cytoplasmic citrate as key regulators of constitutive MICA expression and we propose that metabolic reprogramming of certain cancer cells facilitates MICA expression and NKG2D-mediated immune recognition.
AB - Immune surveillance of cancer cells is facilitated by the Natural Killer Group 2D (NKG2D) receptor expressed by different lymphocyte subsets. It recognizes NKG2D ligands that are rarely expressed on healthy cells, but upregulated by tumorigenesis, presenting a target for immunological clearance. The molecular mechanisms responsible for NKG2D ligand regulation remain complex. Here we report that cancer cell metabolism supports constitutive surface expression of the NKG2D ligand MHC class I chain-related proteins A (MICA). Knockout of the N-glycosylation gene N-acetylglucosaminyltransferase V (MGAT5) in HEK293 cells induced altered metabolism and continuous high MICA surface expression. MGAT5 knockout cells were used to examine the association of cell metabolism and MICA expression through genetic, pharmacological and metabolic assays. Findings were verified in cancer cell lines. Cells with constitutive high MICA expression showed enhanced spare respiratory capacity and elevated mitochondrial efflux of citrate, determined by extracellular flux analysis and metabolomics. MICA expression was reduced by inhibitors of mitochondrial function, FCCP and etomoxir e.g., and depended on conversion of citrate to acetyl-CoA and oxaloacetate by ATP citrate lyase, which was also observed in several cancer cell types. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis revealed that upregulated MICA transcription was associated with an open chromatin structure at the MICA transcription start site. We identify mitochondria and cytoplasmic citrate as key regulators of constitutive MICA expression and we propose that metabolic reprogramming of certain cancer cells facilitates MICA expression and NKG2D-mediated immune recognition.
U2 - 10.3389/fimmu.2020.01968
DO - 10.3389/fimmu.2020.01968
M3 - Journal article
C2 - 32849657
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 1968
ER -
ID: 247987769