Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP

Nikolas G. Tsatsos, Michael N. Davies, Brennon L. O'Callaghan, Howard C. Towle

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

In the liver, induction of genes encoding enzymes involved in de novo lipogenesis occurs in response to increased glucose metabolism. ChREBP (carbohydrate-response-element-binding protein) is a basic helix-loop-helix/ leucine zipper transcription factor that regulates expression of these genes. To evaluate the potential role of ChREBP phosphorylation in its regulation, we used MS to identify modified residues. In the present paper, we report the detection of multiple phosphorylation sites of ChREBP expressed in hepatocytes, several of which are only observed under high-glucose conditions. Mutation of each of these serine/ threonine residues of ChREBP did not alter its ability to respond to glucose. However, mutation of five N-terminal phosphoacceptor sites resulted in a major decrease in activity under high-glucose conditions. These phosphorylated residues are located within a region of ChREBP (amino acids 1-197) that is critical for glucose regulation. Mutation of Ser56 within this region to an aspartate residue resulted in increased nuclear accumulation and activity under high-glucose conditions. Together, these data suggest that ChREBP activity is regulated by complex multisite phosphorylation patterns involving its N-terminal regulatory region.

Original languageEnglish (US)
Pages (from-to)261-270
Number of pages10
JournalBiochemical Journal
Volume411
Issue number2
DOIs
StatePublished - Apr 15 2008

Keywords

  • Carbohydrate-response element-binding protein (ChREBP)
  • Glucose
  • Liver
  • Phosphorylation
  • Transcription factor

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