University of Oulu

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

The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation

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Author: Heidenreich, Steffi1; Weber, Pamela1; Stephanowitz, Heike2;
Organizations: 1Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Berlin, Germany
2Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
3Oulu Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202103107017
Language: English
Published: American Society for Biochemistry and Molecular Biology, 2020
Publish Date: 2021-03-10
Description:

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.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 295
Issue: 50
Pages: 17158 - 17168
DOI: 10.1074/jbc.RA120.014402
OADOI: https://oadoi.org/10.1074/jbc.RA120.014402
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Subjects:
Copyright information: © 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/