title: Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity.
abstract: O-GlcNAcylation is an abundant post-translational modification implicated in human neurodegenerative diseases. We showed that loss-of-function of OGT (O-linked GlcNAc transferase) alleviated, while loss of OGA (O-GlcNAc selective β-N-acetyl-D-glucosaminidase) enhanced, the proteotoxicity of C. elegans neurodegenerative disease models including tauopathy, β-amyloid peptide and polyglutamine expansion. The O-GlcNAc cycling mutants act, in part, by altering insulin signaling, proteasome activity and autophagy. In mutants lacking either of these enzymes of O-GlcNAc cycling, there is a striking accumulation of GFP::LGG-1 (C. elegans homolog of Atg8 and LC3) and increased phosphatidylethanolamine (PE)-modified GFP::LGG-1 upon starvation. We speculate that O-GlcNAc cycling is a key nutrient-responsive regulator of autophagic flux acting at multiple levels including direct modification of BECN1 and BCL2.
authors: Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Peng
authors: P
authors: Wang
authors: John A
authors: JA
authors: Hanover
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D005502:Food; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000633:toxicity*
chemical_list: D029742:Caenorhabditis elegans Proteins; D011506:Proteins; D000117:Acetylglucosamine
keywords: O-GlcNAc; autophagy; insulin signaling; neurodegeneration; proteasome; proteostasis; proteotoxicity