Pyruvate dehydrogenase phosphatase catalytic subunit 2 limits Th17 differentiation

Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9288-9293. doi: 10.1073/pnas.1805717115. Epub 2018 Aug 27.

Abstract

Th17 cells favor glycolytic metabolism, and pyruvate dehydrogenase (PDH) is the key bifurcation enzyme, which in its active dephosphorylated form advances the oxidative phosphorylation from glycolytic pathway. The transcriptional factor, inducible cAMP early repressor/cAMP response element modulator (ICER/CREM), has been shown to be induced in Th17 cells and to be overexpressed in CD4+ T cells from the patients with systemic lupus erythematosus (SLE). We found that glycolysis and lactate production in in vitro Th17-polarized T cells was reduced and that the expression of pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2), an enzyme that converts the inactive PDH to its active form, and PDH enzyme activity were increased in Th17 cells from ICER/CREM-deficient animals. ICER was found to bind to the Pdp2 promoter and suppress its expression. Furthermore, forced expression of PDP2 in CD4+ cells reduced the in vitro Th17 differentiation, whereas shRNA-based suppression of PDP2 expression increased in vitro Th17 differentiation and augmented experimental autoimmune encephalomyelitis. At the translational level, PDP2 expression was decreased in memory Th17 cells from patients with SLE and forced expression of PDP2 in CD4+ T cells from lupus-prone MRL/lpr mice and patients with SLE suppressed Th17 differentiation. These data demonstrate the direct control of energy production during Th17 differentiation in health and disease by the transcription factor ICER/CREM at the PDH metabolism bifurcation level.

Keywords: ICER; PDP2; SLE; Th17; glycolysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Differentiation*
  • Cyclic AMP Response Element Modulator / genetics
  • Cyclic AMP Response Element Modulator / immunology
  • Cyclic AMP Response Element Modulator / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Phosphoprotein Phosphatases / biosynthesis*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / immunology
  • Response Elements*
  • Th17 Cells / enzymology*
  • Th17 Cells / immunology
  • Th17 Cells / pathology

Substances

  • CREM protein, human
  • Crem protein, mouse
  • Cyclic AMP Response Element Modulator
  • Phosphoprotein Phosphatases