Hepatic glucose sensing via the CREB coactivator CRTC2.
Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.
Dentin
Renaud
R
Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Hedrick
Susan
S
Xie
Jianxin
J
Yates
John
J
Montminy
Marc
M
D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D001786:Blood Glucose; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D015534:Trans-Activators; D014157:Transcription Factors; D016695:Glycosyltransferases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D005947:Glucose