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 unfoldedprotein 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 ␤-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-1␣, is attenuated in IRE1␣-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.Nitric oxide, an important mediator of both physiological and pathological processes, has been implicated in the development of a number of inflammatory diseases. When produced at low concentrations, nitric oxide can promote cell growth and survival. At high concentrations, such as those produced during inflammation by inducible nitric oxide synthase (iNOS), nitric oxide induces extensive cellular injury that includes DNA damage, inhibition of oxidative metabolism, and induction of endoplasmic reticulum (ER) stress (5, 12, 39). Pancreatic ␤-cells are exquisitely sensitive to oxidative damage, as glucose-stimulated insulin secretion requires the oxidation of glucose to CO 2 , resulting in the accumulation of ATP. Nitric oxide, produced in micromolar concentrations in response to interleukin 1 (IL-1) and gamma interferon (IFN-␥), mediates the damaging effects of these cytokines on ␤-cell function (3, 33). While nitric oxide stimulates cellular damage, it also activates a number of signaling pathways that limit additional cellular damage and repair existing damage. In pancreatic ␤-cells, the protective responses activated by nitric oxide include (i) JNK-dependent induction of GADD45␣ (growth arrest and DNA damage-inducible protein 45␣) and DNA repair, (ii) activation of AMP-activated protein kinase (AMPK), resulting in enhanced metabolic recovery, and (iii) activation of the unfolded-protein response (UPR) (25,34,38,54,57,61).AMPK is a conserved heterotrimeric (␣, ␤, and ␥ subunits) serine/threonine kinase involved in sensing and responding to the energetic demand within eukaryotic cel...

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

“…Another study showed that quercetin activated AMPK by AMP-dependent and AMP-independent mechanisms [47]. Additionally, quercetin has been shown to activate AMPK via activation of reactive oxygen species generation and inositol-requiring enzyme 1α (IRE1α) RNase [48,49]. The present data also show that PMQ can activate AMPK.…”

Phenformin Activates the Unfolded Protein Response in an AMP-activated Protein Kinase (AMPK)-dependent Manner

“…For example, a recent study showed that the RNase activity of IRE1␣ may be required for nitric oxide-mediated activation of AMPK (53), whereas UPR activation down-regulates the mTOR pathway to enhance autophagy, presumably to provide amino acids by degradation of unnecessary proteins (54). Conversely, AMPK activation reduces translation and attenuates ER stress and UPR (34 -39), similar to our observation.…”

Inositol-Requiring Enzyme 1-Dependent Activation of AMPK Promotes Brucella abortus Intracellular Growth

“…1A) The RNase activity of IRE1 is required for B. abortus infection induced-AMPK activation. IRE1 has been reported to play an important role in mediating AMPK activation in response to ER stress (18). In addition, Brucella intracellular survival can trigger ER stress in host cells (13)(14)(15).…”

“…IRE1, which has been identified to be a necessary protein for B. abortus replication (17), is both a kinase and an endoribonuclease. ER stress is able to induce IRE1-dependent AMPK activation in response to nitric oxide (18). However, the role of IRE1 RNase in mediating AMPK activation during B. abortus infection remains unclear.…”