title: Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer.
abstract: A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven "hexosamine-signaling pathway." A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates O-GlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser- and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3beta (GSK-3beta) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C. elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling "fine-tune" insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C. elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.
authors.affiliation: Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0850, USA.
authors.forename: Michele E
authors.initials: ME
authors.lastname: Forsythe
authors.forename: Dona C
authors.initials: DC
authors.lastname: Love
authors.forename: Brooke D
authors.initials: BD
authors.lastname: Lazarus
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Kim
authors.forename: William A
authors.initials: WA
authors.lastname: Prinz
authors.forename: Gilbert
authors.initials: G
authors.lastname: Ashwell
authors.forename: Michael W
authors.initials: MW
authors.lastname: Krause
authors.forename: John A
authors.initials: JA
authors.lastname: Hanover
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000118:Acetylglucosaminidase / Q000235:genetics* / Q000502:physiology*; D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D004195:Disease Models, Animal; D006595:Hexosamines / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction; D001619:beta-N-Acetylhexosaminidases
chemical_list: D006595:Hexosamines; D007328:Insulin; D009097:Multienzyme Complexes; D051548:Histone Acetyltransferases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine