The hexosamine signaling pathway: deciphering the "O-GlcNAc code".
A dynamic cycle of addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) at serine and threonine residues is emerging as a key regulator of nuclear and cytoplasmic protein activity. Like phosphorylation, protein O-GlcNAcylation dramatically alters the posttranslational fate and function of target proteins. Indeed, O-GlcNAcylation may compete with phosphorylation for certain Ser/Thr target sites. Like kinases and phosphatases, the enzymes of O-GlcNAc metabolism are highly compartmentalized and regulated. Yet, O-GlcNAc addition is subject to an additional and unique level of metabolic control. O-GlcNAc transfer is the terminal step in a "hexosamine signaling pathway" (HSP). In the HSP, levels of uridine 5'-diphosphate (UDP)-GlcNAc respond to nutrient excess to activate O-GlcNAcylation. Removal of O-GlcNAc may also be under similar metabolic regulation. Differentially targeted isoforms of the enzymes of O-GlcNAc metabolism allow the participation of O-GlcNAc in diverse intracellular functions. O-GlcNAc addition and removal are key to histone remodeling, transcription, proliferation, apoptosis, and proteasomal degradation. This nutrient-responsive signaling pathway also modulates important cellular pathways, including the insulin signaling cascade in animals and the gibberellin signaling pathway in plants. Alterations in O-GlcNAc metabolism are associated with various human diseases including diabetes mellitus and neurodegeneration. This review will focus on current approaches to deciphering the "O-GlcNAc code" in order to elucidate how O-GlcNAc participates in its diverse functions. This ongoing effort requires analysis of the enzymes of O-GlcNAc metabolism, their many targets, and how the O-GlcNAc modification may be regulated.
Love
Dona C
DC
Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
Hanover
John A
JA
D000117:Acetylglucosamine / Q000032:analysis / Q000502:physiology*; D000118:Acetylglucosaminidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D000951:Antigens, Neoplasm; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D019295:Computational Biology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006595:Hexosamines / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000502:physiology; D006801:Humans; D006821:Hyaluronoglucosaminidase; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008322:Mammals; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000502:physiology; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D010940:Plant Proteins / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000502:physiology*; D001619:beta-N-Acetylhexosaminidases
D000951:Antigens, Neoplasm; D029742:Caenorhabditis elegans Proteins; D006595:Hexosamines; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D010940:Plant Proteins; D014537:Uridine Diphosphate N-Acetylglucosamine; D051548:Histone Acetyltransferases; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C115866:OGA protein, human; D006821:Hyaluronoglucosaminidase; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine