Glucose Activates ChREBP by Increasing Its Rate of Nuclear Entry and Relieving Repression of Its Transcriptional Activity

Carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that activates genes involved in de novo lipogenesis in mammals. The current model for glucose activation of ChREBP proposes that increased glucose metabolism triggers a cytoplasmic to nuclear translo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-08, Vol.283 (35), p.24029-24038
Main Authors: Davies, Michael N., O'Callaghan, Brennon L., Towle, Howard C.
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - drug effects
Active Transport, Cell Nucleus - physiology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
Cell Line
Cell Nucleus - genetics
Cell Nucleus - metabolism
Cytoplasm - genetics
Cytoplasm - metabolism
Glucose - metabolism
Glucose - pharmacology
Humans
Lipids - biosynthesis
Models, Biological
Mutation
Protein Structure, Tertiary - physiology
Repressor Proteins - genetics
Repressor Proteins - metabolism
Sweetening Agents - metabolism
Sweetening Agents - pharmacology
Transcription, Genetic - drug effects
Transcription, Genetic - physiology
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Summary:Carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that activates genes involved in de novo lipogenesis in mammals. The current model for glucose activation of ChREBP proposes that increased glucose metabolism triggers a cytoplasmic to nuclear translocation of ChREBP that is critical for activation. However, we find that ChREBP actively shuttles between the cytoplasm and nucleus in both low and high glucose in the glucose-sensitive β cell-derived line, 832/13. Glucose stimulates a 3-fold increase in the rate of ChREBP nuclear entry, but trapping ChREBP in the nucleus by mutagenesis or with a nuclear export inhibitor does not lead to constitutive activation. In fact, mutational studies targeting the nuclear export signal of ChREBP also identified a distinct function essential for glucose-dependent transcriptional activation. From this, we conclude that an additional event independent of nuclear translocation is required for activation. The N-terminal segment of ChREBP (amino acids 1-298) has previously been shown to repress activity under basal conditions. This segment has five highly conserved regions, Mondo conserved regions 1-5 (MCR1 to -5). Based on activating mutations in MCR2 and MCR5, we propose that these two regions act coordinately to repress ChREBP in low glucose. In addition, other mutations in MCR2 and mutations in MCR3 were found to prevent glucose activation. Hence, we conclude that both relief of repression and adoption of an activating form are required for ChREBP activation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M801539200