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.
Highlights
Insulin resistance precedes and is a hallmark of type II diabetes [1]
To determine whether adult lifespan extension in oga-1 mutants arises from excessive O-GlcNAc-modifications, we analyzed the lifespan of the oga-1; ogt-1 double mutant which has a markedly reduced level of O-GlcNAc-modified proteins similar to the ogt-1 mutant
The adult lifespan of the oga-1; ogt-1 double mutant is similar to that of wild type (Table 1), confirming that lifespan extension observed in oga-1 mutants is dependent on excessive O-GlcNAc-modified protein levels
Summary
Insulin resistance precedes and is a hallmark of type II diabetes [1]. The onset of insulin resistance is correlated with increased flux through the hexosamine biosynthetic pathway that leads to elevated UDP-N-acetylglucosamine (GlcNAc) from a glycolysis intermediate in mammalian cells [2]. UDP-GlcNAc is the donor for the post-translational modification of nuclear and cytosolic proteins through the addition of an O-linked GlcNAc molecule to serine and threonine residues [3]. Metazoa have conserved O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) enzymes that catalyze the addition and removal of O-GlcNAc, respectively. O-GlcNAc cycling occurs in both the nucleus and cytoplasm, and numerous proteins have been reported to be O-GlcNAc modified including transcription factors, metabolic enzymes, and kinases (reviewed in [4]).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
