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Negative regulation of FOXP3 expression by c-Rel O-GlcNAcylation.

Tristan J de Jesus1, Jeffrey A Tomalka1, Joshua T Centore1

  • 1Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.

Glycobiology
|January 14, 2021
PubMed
Summary

Hyperglycemia increases O-GlcNAcylation of c-Rel, suppressing FOXP3 expression in T cells. This mechanism inversely regulates immunosuppressive and proautoimmune genes in autoimmune diabetes.

Keywords:
NF-kappaBTreg cellsautoimmunitytranscriptiontype 1 diabetes

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Area of Science:

  • Immunology
  • Molecular Biology
  • Metabolic Disease

Background:

  • O-GlcNAcylation is a post-translational modification regulating immune responses and autoimmunity.
  • Hyperglycemia increases O-GlcNAcylation of nuclear factor kappaB c-Rel (c-Rel), enhancing proautoimmune cytokine expression.
  • c-Rel regulates forkhead box P3 (FOXP3), a key transcription factor for regulatory T (Treg) cells.

Purpose of the Study:

  • To investigate the gene-specific regulatory effects of c-Rel O-GlcNAcylation.
  • To determine the impact of c-Rel O-GlcNAcylation on FOXP3 expression in autoimmune diabetes models.
  • To elucidate the mechanism by which O-GlcNAcylation affects c-Rel binding to the FOXP3 promoter.

Main Methods:

  • In vivo studies using streptozotocin-induced and nonobese diabetic mouse models.
  • Analysis of c-Rel binding to the FOXP3 promoter under varying O-GlcNAcylation conditions.
  • Site-directed mutagenesis of the c-Rel O-GlcNAcylation site (Serine 350).

Main Results:

  • c-Rel O-GlcNAcylation suppresses FOXP3 expression in a gene-dependent manner.
  • Hyperglycemia-induced O-GlcNAcylation of c-Rel decreases its binding to the FOXP3 promoter.
  • Mutation of c-Rel Serine 350 augments FOXP3 expression and resists O-GlcNAcylation-dependent repression.

Conclusions:

  • c-Rel S350 O-GlcNAcylation is a novel mechanism inversely regulating FOXP3 and proautoimmune gene expression.
  • This finding highlights a molecular link between hyperglycemia, O-GlcNAcylation, and autoimmune diabetes pathogenesis.
  • Targeting c-Rel O-GlcNAcylation may offer therapeutic potential for autoimmune diseases.