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Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP)
Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP)
- Source :
- Journal of Biological Chemistry. 291:10515-10527
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.
- Subjects :
- 0301 basic medicine
Adenosine monophosphate
biology
Allosteric regulation
Cell Biology
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Cytosol
030104 developmental biology
chemistry
AMP-activated protein kinase
biology.protein
Ketone bodies
Carbohydrate-responsive element-binding protein
Molecular Biology
Transcription factor
Nuclear localization sequence
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 291
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi...........3dfdb42ed720359e944bee4a3edd0891
- Full Text :
- https://doi.org/10.1074/jbc.m115.708982