Authors: Rahman MM; Stuchlick O; El-Karim EG; Stuart R; Kipreos ET; Wells L
Abstract: O-linked-beta-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.
Keywords: Acetylglucosamine/*metabolism; Aging, Premature/genetics; Animals; Caenorhabditis elegans/*physiology; Caenorhabditis elegans Proteins/genetics/metabolism; Cell Nucleus/metabolism; Chromatography, Affinity; Gene Expression/genetics; Glycoproteins/analysis/isolation & purification; Glycosylation; Heat-Shock Proteins/genetics; Insulin/*physiology; Longevity/*physiology; Mutation/genetics; N-Acetylglucosaminyltransferases/genetics; Oxidative Stress/genetics; Phosphatidylinositol 3-Kinases/genetics; Protein Processing, Post-Translational/*physiology; Protein-Serine-Threonine Kinases/genetics; Proto-Oncogene Proteins c-akt/genetics; Receptor, Insulin/genetics; Signal Transduction/*physiology; Superoxide Dismutase/genetics; Transcription Factors/genetics/metabolism; beta-N-Acetylhexosaminidases/genetics|
Journal: Aging Volume: 2 Issue: 10 Pages: 678-90 Date: Oct. 19, 2010 PMID: 20952811 |
Rahman MM, Stuchlick O, El-Karim EG, Stuart R, Kipreos ET, Wells L (2010) Intracellular protein glycosylation modulates insulin mediated lifespan in C.elegans. Aging 2: 678-90.
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