O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene.
Mono-O-glycosylations post-translationally regulate the activity of nucleocytoplasmic proteins. We showed that glucosamine and an inhibitor of deglycosylation (PUGNAc) induced O-glycosylation of FoxO1, resulting in increased expression of a glucose-6-phosphatase reporter gene. This effect was independent of FoxO1 re-localisation, since it was also observed with constitutively nuclear FoxO1-AAA mutant. Moreover, in HepG2 cells, glucosamine and PUGNAc have a synergistic effect on the glucose-6-phosphatase reporter gene, and this effect was inhibited by FoxO1 siRNAs. Since glucose-6-phosphatase plays a key role in hepatic glucose production, our observation may be of importance with regard to glucotoxicity associated with chronic hyperglycaemia in diabetes.
Kuo
Meishiue
M
Institut Cochin, Université Paris Descartes, 22 Rue Méchain, CNRS (UMR 8104), Paris, France.
Zilberfarb
Vladimir
V
Gangneux
Nicolas
N
Christeff
Névéna
N
Issad
Tarik
T
D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D005944:Glucosamine / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D008156:Luciferases; D005952:Glucose-6-Phosphatase; D005944:Glucosamine; D000117:Acetylglucosamine