Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.

Abstract

Nitric oxide (NO) produced from L‐arginine by NO synthases (NOS) is a transmitter known to be involved in diverse biological processes, including immunomodulation, neurotransmission and blood vessel dilatation. We describe a novel role of NO as a signaling molecule in post‐transcriptional gene regulation. We demonstrate that induction of NOS in macrophage and non‐macrophage cell lines activates RNA binding by iron regulatory factor (IRFs), the central trans regulator of mRNAs involved in cellular iron metabolism. NO‐induced binding of IRF to iron‐responsive elements (IRE) specifically represses the translation of transfected IRE‐containing indicator mRNAs as well as the biosynthesis of the cellular iron storage protein ferritin. These findings define a new biological function of NO and identify a regulatory connection between the NO/NOS pathway and cellular iron metabolism.