Abstract
O-linked-β-N-acetylglucosamine (O-GlcNAc) modification is a regulatory, nuclear and cytoplasmic post-translational glycosylation of proteins associated with age-related diseases such as Alzheimer's, Parkinson's, and type II diabetes. Global elevation of O-GlcNAc levels on intracellular proteins can induce insulin resistance, the hallmark of type II diabetes, in mammalian systems. InC. elegans, attenuation of the insulin-like signal transduction pathway increases adult lifespan of the nematode. We demonstrate that the O-GlcNAc cycling enzymes OGT and OGA, which add and remove O-GlcNAc respectively, modulate lifespan in C. elegans. Median adult lifespan is increased in an oga-1 deletion strain while median adult life span is decreased upon ogt-1 deletion. The O-GlcNAc-mediated effect on nematode lifespan is dependent on the FoxO transcription factor DAF-16. DAF-16 is a key factor in the insulin-like signal transduction pathway to regulate reproductive development, lifespan, stress tolerance, and dauer formation in C. elegans. Our data indicates that O-GlcNAc cycling selectively influences only a subset of DAF-16 mediated phenotypes, including lifespan and oxidative stress resistance. We performed an affinity purification of O-GlcNAc-modified proteins and observed that a high percentage of these proteins are regulated by insulin signaling and/or impact insulin pathway functional outcomes, suggesting that the O-GlcNAc modification may control downstream effectors to modulate insulin pathway mediated cellular processes.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylglucosamine / metabolism*
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Aging, Premature / genetics
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Animals
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Cell Nucleus / metabolism
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Chromatography, Affinity
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Forkhead Transcription Factors
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Gene Expression / genetics
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Glycoproteins / analysis
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Glycoproteins / isolation & purification
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Glycosylation
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Heat-Shock Proteins / genetics
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Insulin / physiology*
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Longevity / physiology*
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Mutation / genetics
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N-Acetylglucosaminyltransferases / genetics
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Oxidative Stress / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Protein Processing, Post-Translational / physiology*
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Receptor, Insulin / genetics
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Signal Transduction / physiology*
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Superoxide Dismutase / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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beta-N-Acetylhexosaminidases / genetics
Substances
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Caenorhabditis elegans Proteins
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Forkhead Transcription Factors
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Glycoproteins
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Heat-Shock Proteins
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Insulin
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Transcription Factors
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daf-16 protein, C elegans
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hsp-16.2 protein, C elegans
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Sod-3 protein, C elegans
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Superoxide Dismutase
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N-Acetylglucosaminyltransferases
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O-GlcNAc transferase
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AGE-1 protein, C elegans
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DAF-2 protein, C elegans
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Receptor, Insulin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Sgk-1 protein, C elegans
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akt-1 protein, C elegans
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hexosaminidase C
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beta-N-Acetylhexosaminidases
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Acetylglucosamine