Nitric oxide: A regulator of eukaryotic initiation factor 2 kinases

Generation of nitric oxide (NO
- ) can upstream induce and downstream mediate the kinases that phosphorylate the α subunit of eukaryotic initiation factor 2 (eIF2α), which plays a critical role in regulating gene expression. There are four known eIF2α kinases (EIF2AKs), and NO
- affects each one uniquely. Whereas NO
- 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
- . Finally EIF2AK2 (PKR), which can mediate inducible NOS expression and therefore NO
- production, can also be activated by NO
- . The production of NO
- and activation of EIF2AKs coordinately regulate physiological and pathological events such as innate immune response and cell apoptosis.