IRE1-dependent activation of AMPK in response to nitric oxide

The University of Alabama at Birmingham, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Birmingham, Alabama 352941, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 09/2011; 31(21):4286-97. DOI: 10.1128/MCB.05668-11
Source: PubMed


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.

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    • "Moreover, IRE1α activation is increased and RACK1 abundance is decreased in db/db mice [57]. The endoplasmic activity of IRE1α is also involved in the activation of a key metabolic enzyme, AMP-activated kinase (AMPK), in response to nitric oxide (NO) and ER stress in β cells [58]. AMPK is a holoenzyme activated by changes in AMP/ATP ratio, shifting from glucose to the use of lipids as an energy source in order to respond to cellular demand [59]. "
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    • "However, cross talk between the UPR and master metabolic regulators has received little attention until recently. AMPK has been shown to require the endoribonuclease activity of IRE1 for nitric oxide-induced signaling (Meares et al., 2011). Moreover, stimulation of the IRE1 endoribonuclease activity with the flavonoid quercetin also engages IRE1-dependent AMPK activation . "
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