Abstract
We have recently identified ferritin as a cellular protein particle whose synthesis is stimulated in mouse or human cells infected by the picornavirus Mengo. Immunoprecipitation of the particle from infected murine L929 cells showed a 4- and 6-fold increase in the intracellular concentrations of H and L apoferritin subunits, respectively. This differential expression altered the H/L subunit ratio from 3.0 in uninfected cells to 2.2 in Mengo virus-infected cells. The induction is not due to an increase in transcription of the apoferritin L and H genes, nor is it due to an increase in stability of the apoferritin mRNAs. At the level of translation, the iron regulatory protein (IRP) remained intact, with similar amounts being detected in uninfected and infected cells. The Mengo virus RNA genome does not compete with the iron regulatory element (IRE) for the binding of IRP, and sequence analysis confirmed that there are no IREs in the virus RNA. The IRE binding activity of IRP in infected cells decreased approximately 30% compared with uninfected cells. The decrease in binding activity could be overcome by the addition of Desferal (deferoxamine mesylate; CIBA) an intracellular iron chelator, which suggests that virus infection causes an increase in intracellular free iron. Electron paramagnetic resonance (EPR) studies have confirmed the increase in free iron in Mengo virus infected cells. The permeability of cells for iron does not change in virus infected cells, suggesting that the induction of ferritin by Mengo virus is due to a change in the form of intracellular iron from a bound to a free state.
Highlights
Free ferrous or ferric iron in biological systems can catalyze a number of reactions which generate free radicals and can lead to protein, DNA, and/or lipid damage
The role of iron or hemin in the induction of transcription of the two apoferritin genes is dependent on the particular cell line tested: free iron has been shown to increase the levels of L and H apoferritin mRNA in human myoblasts [4], human K562 cells [12], mouse fibroblasts, and Chinese hamster ovary cells [13]; this did not occur in human HeLa cells [13]
Mengo Virus Infection Induces the Synthesis of Apoferritin—To determine the amounts of synthesis of each of the two apoferritin subunits that were induced by Mengo virus, L929 fibroblasts were infected, metabolically labeled with [35S]methionine 4 h after infection, and lysed 1 h later
Summary
Free ferrous or ferric iron in biological systems can catalyze a number of reactions which generate free radicals and can lead to protein, DNA, and/or lipid damage. The translational control of apoferritin is mediated by a 98-kDa “iron regulatory protein-1” (IRP-1), previously referred to as the “iron regulatory factor” (IRF; Ref. 14), the “iron response element-binding protein” (IRE-BP; Ref. 15), or the “ferritin repressor protein” (Ref. 16). IRP-2 has a molecular mass of 105 kDa and is structurally related to, but distinct from, IRP-1 [27, 29] It has similar affinity for IREs but lacks aconitase activity and, unlike IRP-1, is rapidly degraded in cells supplemented with iron (28 –32). Ferritin Induction by Mengo Virus during liver regeneration in the absence of changes in total tissue iron content [33]
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