The University of Alabama at Birmingham, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Birmingham, Alabama 352941, USA.
Mol Cell Biol. 2011 Nov;31(21):4286-97. doi: 10.1128/MCB.05668-11. Epub 2011 Sep 6.
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.
虽然一氧化氮在病理浓度下会产生有害的后果，但真核细胞已经进化出了保护机制来抵御这种损伤。未折叠蛋白反应（UPR）是一种适应性机制，可激活由错误折叠的蛋白质和氧化应激引起的细胞，以保护细胞免受应激。一氧化氮是 AMP 激活蛋白激酶（AMPK）的有效激活剂，AMPK 参与了胰腺β细胞中一氧化氮介导的损伤的细胞防御。在这项研究中，探索了一氧化氮激活 AMPK 的机制。已知的 AMPK 激酶 LKB1、CaMKK 和 TAK1 对于一氧化氮激活 AMPK 并不必需。相反，这种激活依赖于内质网（ER）应激激活蛋白 IRE1。IRE1α 缺陷细胞中，一氧化氮诱导的 AMPK 磷酸化及其随后对 AMPK 底物（包括 Raptor、乙酰辅酶 A 羧化酶和 PGC-1α）的信号转导减弱。IRE1 的内切核酸酶活性似乎是一氧化氮诱导的 AMPK 激活所必需的。除了一氧化氮外，用类黄酮槲皮素刺激 IRE1 的内切核酸酶活性也会导致 IRE1 依赖性 AMPK 激活。这些发现表明，IRE1 的核糖核酸酶活性参与了 AMPK 激活，并通过多种 AMPK 依赖性途径在应激条件下参与了随后的信号转导。
