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PMID:16882729

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Citation

Forsythe, ME, Love, DC, Lazarus, BD, Kim, EJ, Prinz, WA, Ashwell, G, Krause, MW and Hanover, JA (2006) Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc. Natl. Acad. Sci. U.S.A. 103:11952-7

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.

Links

PubMed PMC1567679 Online version:10.1073/pnas.0601931103

Keywords

Acetylglucosamine/metabolism; Acetylglucosaminidase/genetics; Acetylglucosaminidase/physiology; Alleles; Animals; Animals, Genetically Modified; Caenorhabditis elegans/physiology; Disease Models, Animal; Hexosamines/metabolism; Histone Acetyltransferases/genetics; Histone Acetyltransferases/physiology; Insulin/metabolism; Insulin Resistance; Molecular Sequence Data; Multienzyme Complexes/genetics; Multienzyme Complexes/physiology; Mutation; Phosphorylation; Signal Transduction; beta-N-Acetylhexosaminidases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:A8WFI7

enables

GO:0015929: hexosaminidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0019915: lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0009100: glycoprotein metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0009100: glycoprotein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:A8WFI7

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

F

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0005977: glycogen metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:A8WFI7

involved_in

GO:0040024: dauer larval development

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:OGT1

involved_in

GO:0019915: lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete

CAEEL:OGT1

involved_in

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete

CAEEL:OGT1

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

F

Seeded From UniProt

complete

CAEEL:OGT1

involved_in

GO:0005977: glycogen metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

enables

GO:0015929: hexosaminidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0019915: lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0009100: glycoprotein metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0009100: glycoprotein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

F

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0005977: glycogen metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092462

P

Seeded From UniProt

complete

CAEEL:Q1WBU8

involved_in

GO:0040024: dauer larval development

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:Q2L6Y4

involved_in

GO:0005977: glycogen metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete

CAEEL:Q2L6Y4

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

F

Seeded From UniProt

complete

CAEEL:Q2L6Y4

involved_in

GO:0019915: lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete

CAEEL:Q2L6Y4

involved_in

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091724

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.