RESEARCH PAPER

AGING, Vol 2, No 10 , pp 678-690
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Intracellular protein glycosylation modulates insulin mediated lifespan in C. elegans

Mohammad M. Rahman1, Olga Stuchlick2, Enas G. El-Karim2, Ryan Stuart2, Edward T. Kipreos3, and Lance Wells2
1 Department of Genetics, University of Georgia, Athens, GA 30602, USA
2 Department of Biochemistry & Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
3 Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
Key words:
C. elegans, lifespan, O-GlcNAc, OGT, OGA
Abbreviations:
O-GlcNAc, O-linked b-N-acetylglucosamine; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase (neutral b-N-acetylglucosaminidase); PI3K, phosphatidylinositol-3-OH kinase
Received:
10/01/10; accepted: 10/13/10; published on line: 10/14/10
Corresponding authors:
E-mail:

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.