The selenium metabolite methylselenol regulates the expression of ligands that trigger immune activation through the lymphocyte receptor NKG2D

TY - JOUR

T1 - The selenium metabolite methylselenol regulates the expression of ligands that trigger immune activation through the lymphocyte receptor NKG2D

AU - Hagemann-Jensen, Michael Henrik

AU - Uhlenbrock, Franziska Katharina

AU - Kehlet, Stephanie

AU - Andresen, Lars

AU - Gabel-Jensen, Charlotte

AU - Ellgaard, Lars

AU - Gammelgaard, Bente

AU - Skov, Søren

N1 - Copyright © 2014, The American Society for Biochemistry and Molecular Biology.

PY - 2014/11/7

Y1 - 2014/11/7

N2 - 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 ofDNAdamage, 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 MHCclass 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.

AB - 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 ofDNAdamage, 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 MHCclass 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.

U2 - 10.1074/jbc.M114.591537

DO - 10.1074/jbc.M114.591537

M3 - Journal article

C2 - 25258323

SN - 0021-9258

VL - 289

SP - 31576

EP - 31590

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

ER -