title: IRE1-dependent activation of AMPK in response to nitric oxide.
abstract: While there can be detrimental consequences of nitric oxide production at pathological concentrations, eukaryotic cells have evolved protective mechanisms to defend themselves against this damage. The unfolded-protein response (UPR), activated by misfolded proteins and oxidative stress, is one adaptive mechanism that is employed to protect cells from stress. Nitric oxide is a potent activator of AMP-activated protein kinase (AMPK), and AMPK participates in the cellular defense against nitric oxide-mediated damage in pancreatic β-cells. In this study, the mechanism of AMPK activation by nitric oxide was explored. The known AMPK kinases LKB1, CaMKK, and TAK1 are not required for the activation of AMPK by nitric oxide. Instead, this activation is dependent on the endoplasmic reticulum (ER) stress-activated protein IRE1. Nitric oxide-induced AMPK phosphorylation and subsequent signaling to AMPK substrates, including Raptor, acetyl coenzyme A carboxylase, and PGC-1α, is attenuated in IRE1α-deficient cells. The endoribonuclease activity of IRE1 appears to be required for AMPK activation in response to nitric oxide. In addition to nitric oxide, stimulation of IRE1 endoribonuclease activity with the flavonol quercetin leads to IRE1-dependent AMPK activation. These findings indicate that the RNase activity of IRE1 participates in AMPK activation and subsequent signaling through multiple AMPK-dependent pathways in response to nitrosative stress.
authors: The University of Alabama at Birmingham, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Birmingham, Alabama 352941, USA.
authors: Gordon P
authors: GP
authors: Meares
authors: Katherine J
authors: KJ
authors: Hughes
authors: Aaron
authors: A
authors: Naatz
authors: Feroz R
authors: FR
authors: Papa
authors: Fumihiko
authors: F
authors: Urano
authors: Polly A
authors: PA
authors: Hansen
authors: Etty N
authors: EN
authors: Benveniste
authors: John A
authors: JA
authors: Corbett
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes; D009569:Nitric Oxide / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D004722:Endoribonucleases; D020930:MAP Kinase Kinase Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C486557:Ern2 protein, rat; C510185:Ern1 protein, mouse; C488755:Stk11 protein, rat