Intracellular protein glycosylation modulates insulin mediated lifespan in C.elegans.
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.
Department of Genetics, University of Georgia, Athens, 30602, USA.
Mohammad M
MM
Rahman
Olga
O
Stuchlick
Enas G
EG
El-Karim
Ryan
R
Stuart
Edward T
ET
Kipreos
Lance
L
Wells
D000117:Acetylglucosamine / Q000378:metabolism*; D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002846:Chromatography, Affinity; D051858:Forkhead Transcription Factors; D015870:Gene Expression / Q000235:genetics; D006023:Glycoproteins / Q000032:analysis / Q000302:isolation & purification; D006031:Glycosylation; D006360:Heat-Shock Proteins / Q000235:genetics; D007328:Insulin / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics
D000117:Acetylglucosamine; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; D006360:Heat-Shock Proteins; D007328:Insulin; D017351:N-Acetylglucosaminyltransferases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011972:Receptor, Insulin; D013482:Superoxide Dismutase; D014157:Transcription Factors; D001619:beta-N-Acetylhexosaminidases; C108831:daf-16 protein, C elegans; C108431:hsp-16.2 protein, C elegans; C525107:Sod-3 protein, C elegans; C449880:O-GlcNAc transferase; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans; C540745:Sgk-1 protein, C elegans; C494915:akt-1 protein, C elegans; C110628:hexosaminidase C