IRE1-dependent activation of AMPK in response to nitric oxide. Mol Cell Biol 2011 Nov;31(21):4286-97
Date
09/08/2011Pubmed ID
21896783Pubmed Central ID
PMC3209336DOI
10.1128/MCB.05668-11Scopus ID
2-s2.0-83255187905 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
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.
Author List
Meares GP, Hughes KJ, Naatz A, Papa FR, Urano F, Hansen PA, Benveniste EN, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAnimals
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Cell Line
Endoplasmic Reticulum Stress
Endoribonucleases
Enzyme Activation
Gene Knockdown Techniques
Insulin-Secreting Cells
MAP Kinase Kinase Kinases
Mechanistic Target of Rapamycin Complex 1
Membrane Proteins
Mice
Models, Biological
Multiprotein Complexes
Nitric Oxide
Proteins
RNA, Small Interfering
Rats
Signal Transduction
TOR Serine-Threonine Kinases
