The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation
Heidenreich, Steffi; Weber, Pamela; Stephanowitz, Heike; Petricek, Konstantin M.; Schütte, Till; Oster, Moritz; Salo, Antti M.; Knauer, Miriam; Goehring, Isabel; Yang, Na; Witte, Nicole; Schumann, Anne; Sommerfeld, Manuela; Muenzner, Matthias; Myllyharju, Johanna; Krause, Eberhard; Schupp, Michael (2021-01-13)
Steffi Heidenreich, Pamela Weber, Heike Stephanowitz, Konstantin M. Petricek, Till Schütte, Moritz Oster, Antti M. Salo, Miriam Knauer, Isabel Goehring, Na Yang, Nicole Witte, Anne Schumann, Manuela Sommerfeld, Matthias Muenzner, Johanna Myllyharju, Eberhard Krause, Michael Schupp, The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation, Journal of Biological Chemistry, Volume 295, Issue 50, 2020, Pages 17158-17168, ISSN 0021-9258, https://doi.org/10.1074/jbc.RA120.014402
© 2020 Heidenreich et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the CC BY license.
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe202103107017
Tiivistelmä
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.
Kokoelmat
- Avoin saatavuus [34589]