Feedback regulation of o-glcnac transferase through translation control to maintain intracellular o-glcnac homeostasis

Chia Hung Lin, Chen Chung Liao, Mei Yu Chen*, Teh Ying Chou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Protein O-GlcNAcylation is a dynamic post-translational modification involving the attachment of N-acetylglucosamine (GlcNAc) to the hydroxyl groups of Ser/Thr residues on numer-ous nucleocytoplasmic proteins. Two enzymes are responsible for O-GlcNAc cycling on substrate proteins: O-GlcNAc transferase (OGT) catalyzes the addition while O-GlcNAcase (OGA) helps the removal of GlcNAc. O-GlcNAcylation modifies protein functions; therefore, dysregulation of O-GlcNAcylation affects cell physiology and contributes to pathogenesis. To maintain homeostasis of cellular O-GlcNAcylation, there exists feedback regulation of OGT and OGA expression responding to fluctuations of O-GlcNAc levels; yet, little is known about the molecular mechanisms involved. In this study, we investigated the O-GlcNAc-feedback regulation of OGT and OGA expression in lung cancer cells. Results suggest that, upon alterations in O-GlcNAcylation, the regulation of OGA expression occurs at the mRNA level and likely involves epigenetic mechanisms, while modulation of OGT expression is through translation control. Further analyses revealed that the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) contributes to the downregulation of OGT induced by hyper-O-GlcNAcylation; the S5A/S6A O-GlcNAcylation-site mutant of 4E-BP1 cannot support this regulation, suggesting an important role of O-GlcNAcylation. The results provide additional insight into the molecular mechanisms through which cells may fine-tune intracellular O-GlcNAc levels to maintain homeostasis.

Original languageEnglish
Article number3463
JournalInternational Journal Of Molecular Sciences
Volume22
Issue number7
DOIs
StatePublished - 1 Apr 2021

Keywords

  • Epigenetics
  • Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)
  • His-tone deacetylase (HDAC)
  • O-GlcNAc homeostasis
  • O-GlcNAc transferase (OGT)
  • O-GlcNAcase (OGA)
  • O-GlcNAcylation
  • O-linked N-acetylglucosamine (O-GlcNAc)
  • Post-translational modification
  • Translation control

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