Post-transcriptional regulation of genes of iron metabolism in mammalian cells

Abstract

 Iron metabolism is tightly regulated in mammalian cells. Here we describe several types of post-transcriptional mechanisms that have been identified in regulation of genes of iron metabolism. Iron-dependent regulation of stability of the transcript is the key to regulation of the expression of the transferrin receptor. Selective repression of translation in iron-depleted cells is the key to regulation of the expression of ferritin and several other genes that require iron for function. Specific regulatory proteins that directly sense iron levels in cells are needed to coordinate iron metabolism. These proteins, known as iron regulatory proteins (IRPs), bind to specific RNA stem-loops in transcripts with high affinity when cells are depleted of iron. The two IRPS, IRP1 and IRP2, are post-translationally modified by iron, but the nature of the post-translational regulatory process differs. IRP1 assembles an iron-sulfur cluster which determines its function, whereas IRP2 is rapidly degraded in the presence of iron. Direct binding of iron is likely to be involved in sensing of iron levels by IRP1 and IRP2. Although each IRP binds to the RNA stem-loop motifs known as iron-responsive elements (IREs) with high affinity, it is possible that each protein binds an additional, unique set of target-binding motifs. The list of potential genes that are regulated by IRPs continues to grow, and much remains to be learned about the regulation of mammalian iron metabolism.