Nitric oxide: A regulator of eukaryotic initiation factor 2 kinases

Generation of nitric oxide (NO(center dot)) can upstream induce and downstream mediate the kinases that phosphorylate the a subunit of eukaryotic initiation factor 2 (eIF2 alpha), which plays a critical role in regulating gene expression. There are four known eIF2 alpha kinases (EIF2AKs), and NO(center dot) affects each one uniquely. Whereas NO(center dot) directly activates EIF2AK1 (HRI), it indirectly activates EIF2AK3 (PERK). EIF2AK4 (GCN2) is activated by depletion of L-arginine, which is used by nitric oxide synthase (NOS) during the production of NO(center dot). Finally EIF2AK2 (PKR), which can mediate inducible NOS expression and therefore NO(center dot) production, can also be activated by NO(center dot). The production of NO(center dot) and activation of EIF2AKs coordinately regulate physiological and pathological events such as innate immune response and cell apoptosis. (C) 2011 Elsevier Inc. All rights reserved.