Ferritin mRNA translation

Thomson AM, Rogers IT, Leedman PJ. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int. J. Biochem. Cell. Biol. 1999 31 1139-1152. 

Toth, I., and Bridget, K. R. (1995). Ascrobic acid enhances ferritin mRNA translation by an IRP/aconit0se switch. /. Bioi Citem. 270, 19540-19544. 

The identification of H2O2 as a signaling molecule for IRPl establishes a direct regulatory link between iron metabolism and oxidative stress [140, 141]. The rapid and prolonged H202-mediated induction of IRPl to bind to IREs results in inhibition of ferritin mRNA translation and increased TfR mRNA levels [140]. These cellular responses are predicted to contribute to an increase in intracellular iron con-... 

Plants Iron signals are transduced to relieve trans-acting factors and derepress ferritin gene transcription. Animals Iron signals are transduced to relieve IRP binding to IREs and derepress ferritin mRNA translation. 

Walden WE, Daniels McQueen S, Brown PH, Gaffield L, Russell DA, Bielser D, Bailey LD, Thach RE (1988) Translational repression in eukaryotes partial purification and characterization of a repressor of ferritin mRNA translation. Proc Natl Acad Sci USA 85 9503-9507... 

Another example of mRNA masking is suggested by the iron-induced synthesis of ferritin. In reticulocytes of the bullfrog tadpole, synthesis of ferritin increases 40- to 50-fold in the presence of iron, while the level of ferritin mRNA, translatable after extraction in the... 

In the next section we will outline briefly how IRPs control intracellular iron homeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability [53,54]. 

The iron regulatory proteins, IRP-1 and IRP-2, bind at high affinity (Kd 40-100 pM) to highly conserved RNA stemloops, the Iron-responsive Elements (IREs) at the 5 cap sites of the L- and H-ferritin niRNAs [55-57] (Figure 2). The IRE/IRP interaction impedes the access of the small 40S ribosome subunit to the 5 end of the ferritin niRNAs and thereby suppresses L- and H-ferritin mRNA translation [58-60]. The potency of the IRE to regulate translation is position dependent [61]. Iron influx relieves repression of ferritin translation by removing IRP-1 from the ferritin IREs IRP-1 is simultaneously interconverted to a cytoplasmic cis-aconitase with an iron sulfur cluster, and IRP-2 is degraded by... 

Figure 1. Intracellular Iron Homeostasis. Iron transit across the cell surface membrane is mediated by (i) ferrotransferrin internalization by the transferrin receptor (TfR), (ii) DMT-1, (Hi) ferroportin mediated iron efflux from the duodenum into the blood. Ferritin mRNA translation is regulated by the modulated interaction between the IRPs and the IREs in the 5 UTR of ferritin mRNA. MAP kinase signaling events influence ferritin translation and transferrin receptor activity and expression.

Figure 2. Model for Ferritin mRNA Translational Control Iron releases IRP-l/IRP-2 from suppressing ferritin mRNA translation at the Iron responsive Element stemloops (IREs) specific to the L- and H- mRNA 5 cap sites. In the diagram, IRP-I and IRP-2 are depicted as two domains separated by a hinge region (line). Our preliminary data suggests that the RNA binding protein (Poly C-binding proteins, CP-1 and CP-2) interact with the ferritin mRNA acute box(AB) domain (box) downstream from the IRE (Thomson et al. In revision).

Ferritin, an iron-binding protein, prevents ionized iron (Fe ) from reaching toxic levels within cells. Elemental iron stimulates ferritin synthesis by causing the release of a cytoplasmic protein that binds to a specific region in the 5 nontranslated region of ferritin mRNA. Disruption of this protein-mRNA interaction activates ferritin mRNA and results in its translation. This mechanism provides for rapid control of the synthesis of a protein that sequesters Fe +, a potentially toxic molecule. 

Synthesis of the transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content. Specific untranslated sequences of the mRNAs for both proteins (named iron response elements) interact with a cytosolic protein sensitive to variations in levels of cellular iron (iron-responsive element-binding protein). When iron levels are high, cells use stored ferritin mRNA to synthesize ferritin, and the TfR mRNA is degraded. In contrast, when iron levels are low, the TfR mRNA is stabilized and increased synthesis of receptors occurs, while ferritin mRNA is apparently stored in an inactive form. This is an important example of control of expression of proteins at the translational level. 

TRANSLATION/RIBOSOME BINDING ELEMENT (Ferritin mRNAs, 5TJTR)... 

Figure 7.4 (a) IREs in eukaryotic mRNAs the secondary structures of ferritin and transferrin receptor IREs. (b) The IRE localization in mRNAs the translation/ribosome binding element in the 5 -UTR of ferritin mRNA is above, that of the stability/ turnover element in the 3 -UTR of transferrin receptor mRNA is below. Adapted from Theil, 1998, by courtesy of Marcel Dekker, Inc. 

Figure 8.15 IRE in ferritin mRNA from Crichton (2001) and outline of translational regulation of mRNAs of a number of proteins involved in iron metabolism in low and high iron. (From Wallander et al., 2006. Copyright 2006, with permission from Elsevier.)...

Consider ferritin first. Ferritin mRNA includes a stem-loop structure termed an iron-response element (IRE) in its 5 untranslated region (Figure 31.38). This stem-loop binds a 90-kd protein, czAlsd m IRE-bindingprotein (IRE-BP), that blocks the initiation of translation. When the iron level increases, the IRE-BP binds iron as a 4Fe-4S cluster. The IRE-BP bound to iron cannot bind RNA, because the binding sites for iron and RNA substantially overlap. Thus, in the presence of iron, ferritin mRNA is released from the IRE-BP and translated to produce ferritin, which sequesters the excess iron. 

Figure 31.38. Iron-Response Element. Ferritin mRNA includes a stem-loop structure, termed an iron-response element (IRE), in its 5 untranslated region. The IRE binds a specific protein that blocks the translation of this mRNA under low...

A rapid translational response of ferritin has been reported to occur after ferritin mRNA was recruited to polysomes [14]. An increase in the cytosolic ferritin mRNA and ferritin protein following ischemia and reperfiision of the intestine was also reported [26]. Reperfusion has been shown to cause ferritin degradation, followed by activation of ferritin synthesis [27,28]. 

It is proposed that during the PC phase small, but significant, levels of intracellular iron undergo re-distribution and mobilization. This, in turn, produces the necessary signal for enhanced translation of ferritin mRNA, increasing its level and its capacity to scavenge and store iron. 

When iron is low in the cell, the mRNA for ferritin is translated at a lesser rate (resulting in lesser amoimts of this protein in the cell). The goal here is to cut down on the excessive synthesis of our major iron storage protein, if no excess iron is available for storing. When iron is low in the cell, the mRNA for the transferrin receptor is translated more (creating more transferrin). When iron is low in the cell, the mRNA for 5-aminolevulinate synthase, an enz)mie in the heme biosynthetic pathway, is translated less. The overall goal here is to cut down on the wasteful synthesis of heme, if no iron is available for completing this cofactor. 

Coordinate translational regulation of ferritin mRNA and transferrin receptor mRNA in nonerythroid cells. Iron regulatory proteins (IRP) are RNA-binding proteins that bind to iron regulatory elements (IREs). IREs are hairpin structures with loops consisting of CAGUGN sequences and are located at the 5 -untranslated region (UTR) and 3 -UTR for ferritin mRNA and transferrin mRNA, respectively. 

---