INVOLVEMENT OF HEME IN THE DEGRADATION OF IRON-REGULATORY PROTEIN-2

Iron-regulatory proteins (IRPs) recognize and bind to specific RNA str uctures called iron-responsive elements. Mediation of these binding in teractions by iron and iron-containing compounds regulates several pos ttranscriptional events relevant to iron metabolism. There are two kno wn IRPs, IRP1 and IRP2, both of which can respond to iron fluxes in th e cell. There is ample evidence that IRP1 is converted by iron to cyto plasmic aconitase in vivo. It has also been shown that, under certain conditions, a significant fraction of IRP1 is degraded in cells expose d to iron or heme. Studies have shown that the degradation of IRP1 tha t is induced by iron can be inhibited by either desferrioxamine mesyla te (an iron chelator) or succinyl acetone (an inhibitor of heme synthe sis), whereas the degradation induced by heme cannot. This suggests th at heme rather than iron is responsible for this degradation. Several laboratories have shown that IRP2 is also degraded in cells treated wi th iron salts. We now show evidence suggesting that this IRP2 degradat ion may be mediated by heme. Thus, in experiments analogous to those u sed previously to study IRP1, we find that IRP2 is degraded in rabbit fibroblast cells exposed to heme or iron salts. However, as shown earl ier with IRP1, both desferrioxamine mesylate and succinyl acetone will inhibit the degradation of IRP2 induced by iron but not that induced by heme.