1. The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation
- Author
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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, and Miriam Knauer more...
- Subjects
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 - Abstract
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. more...
- Published
- 2020