Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway

J Immunol. 2010 Sep 15;185(6):3498-503. doi: 10.4049/jimmunol.1001250. Epub 2010 Aug 20.


Most cancer cells use anaerobic-like glycolysis to generate energy instead of oxidative phosphorylation. They also avoid recognition by CTLs, which occurs primarily through decreasing the level of MHC class I (MHC-I) at the cell surface. We find that the two phenomena are linked; culture conditions that force respiration in leukemia cells upregulate MHC-I transcription and protein levels at the cell surface, whereas these decrease in cells forced to perform fermentation as well as in leukemia cells lacking a functional mitochondrial respiratory chain. Forced respiration leads to increased expression of the MAPK ERK5, which activates MHC-I gene promoters, and ERK5 accumulation in mitochondria. Respiration-induced MHC-I upregulation is reversed upon short hairpin RNA-mediated ERK5 downregulation and by inactive mutants of ERK5. Moreover, short hairpin RNA for ERK5 leukemia cells do not tolerate forced respiration. Thus, the expression of ERK5 and MHC-I is linked to cell metabolism and notably diminished by the metabolic adaptations found in tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / immunology
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Down-Regulation / immunology
  • Gene Expression Regulation / immunology*
  • Glutamine / metabolism
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Jurkat Cells
  • Leukemia L1210
  • Leukemia, B-Cell / enzymology
  • Leukemia, B-Cell / immunology*
  • Leukemia, B-Cell / pathology
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology*
  • Mice
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / physiology*
  • Oxidative Phosphorylation*
  • Up-Regulation / immunology


  • Histocompatibility Antigens Class I
  • Glutamine
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase 7