AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation.
We have demonstrated previously that a wide array of stress signals induces O-GlcNAc transferase (OGT) expression and increases O-GlcNAcylation of many intracellular proteins, a response that is critical for cell survival. Here, we describe a mechanism by which glucose deprivation induces OGT expression and activity in Neuro-2a neuroblastoma cells. Glucose deprivation increases OGT mRNA and protein expression in an AMP-activated protein kinase-dependent manner, whereas OGT enzymatic activity is regulated in a p38 MAPK-dependent manner. OGT is not phosphorylated by p38, but rather it interacts directly with p38 through its C terminus; this interaction increases with p38 activation during glucose deprivation. Surprisingly, the catalytic activity of OGT, as measured toward peptide substrates, is not altered by glucose deprivation. Instead, p38 regulates OGT activity within the cell by recruiting it to specific targets, including neurofilament H. Neurofilament H is O-GlcNAcylated during glucose deprivation in a p38-dependent manner. Interestingly, neurofilament H solubility is increased by glucose deprivation in an O-GlcNAc-dependent manner, suggesting that O-GlcNAcylation of neurofilament H regulates its disassembly from filaments. Not only do these data help to reveal how OGT is regulated by stress, but these findings also describe a possible mechanism by which defective brain glucose metabolism, as found in aging and ischemia, may directly affect axonal structure.
Cheung
Win D
WD
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185, USA.
Hart
Gerald W
GW
D055372:AMP-Activated Protein Kinases; D000215:Acylation; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012995:Solubility; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D009097:Multienzyme Complexes; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose