The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation
| Autor: | Manuela Sommerfeld, Na Yang, Matthias Muenzner, Konstantin M. Petricek, Nicole Witte, Michael Schupp, Pamela Weber, Antti M. Salo, Till Schütte, Isabel Goehring, Anne Schumann, Steffi Heidenreich, Heike Stephanowitz, Moritz Oster, Johanna Myllyharju, Eberhard Krause, Miriam Knauer |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male post-translational modification (PTM) proline hydroxylation Proline ChREBP carbohydrate function glucose metabolism Mice Transgenic Carbohydrate metabolism Hydroxylation Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice Metabolic Diseases Transcriptional regulation hepatocyte hydroxyproline Animals Humans Glycolysis Gene Regulation Carbohydrate-responsive element-binding protein Molecular Biology Transcription factor 030102 biochemistry & molecular biology glucose sensing Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cell Biology Cell biology 030104 developmental biology Glucose HEK293 Cells chemistry Gene Expression Regulation Liver Lipogenesis Flux (metabolism) Protein Processing Post-Translational |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases. |
| Databáze: | OpenAIRE |
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