title: A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome.
abstract: Protein-O-linked N-Acetyl-β-D-glucosaminidase (O-GlcNAcase, OGA; also known as hexosaminidase C) participates in a nutrient-sensing, hexosamine signaling pathway by removing O-linked N-acetylglucosamine (O-GlcNAc) from key target proteins. Perturbations in O-GlcNAc signaling have been linked to Alzheimer's disease, diabetes and cancer. Mammalian O-GlcNAcase exists as two major spliced isoforms differing only by the presence (OGA-L) or absence (OGA-S) of a histone-acetyltransferase domain. Here we demonstrate that OGA-S accumulates on the surface of nascent lipid droplets with perilipin-2; both of these proteins are stabilized by proteasome inhibition. We show that selective downregulation of OGA-S results in global proteasome inhibition and the striking accumulation of ubiquitinylated proteins. OGA-S knockdown increased levels of perilipin-2 and perilipin-3 suggesting that O-GlcNAc-dependent regulation of proteasomes might occur on the surface of lipid droplets. By locally activating proteasomes during maturation of the nascent lipid droplet, OGA-S could participate in an O-GlcNAc-dependent feedback loop regulating lipid droplet surface remodeling. Our findings therefore suggest a mechanistic link between hexosamine signaling and lipid droplet assembly and mobilization.
authors.affiliation: Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Chithra N
authors.initials: CN
authors.lastname: Keembiyehetty
authors.forename: Anna
authors.initials: A
authors.lastname: Krzeslak
authors.forename: Dona C
authors.initials: DC
authors.lastname: Love
authors.forename: John A
authors.initials: JA
authors.lastname: Hanover
mesh_terms: D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000070780:Perilipin-2; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000648:ultrastructure; D061988:Proteasome Inhibitors; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008565:Membrane Proteins; D000070780:Perilipin-2; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C063261:acetylleucyl-leucyl-norleucinal; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D046988:Proteasome Endopeptidase Complex