Low Cytosolic Non-Heme Iron Levels in Erythroid Cells Prevent IRP2-Mediated Ferritin Upregulation during Differentiation.
Notice bibliographique
Résumé
Abstract Erythroid cells are the major consumers of iron in the human body. Differentiating erythroid cells shuttle the metal with very high efficiency towards mitochondria for the formation of heme. To satisfy their high iron needs, developing red blood cells (RBC) have to sustain high expression of transferrin receptor 1 (TfR) despite increasing cellular iron concentration. Moreover, synthesis of ferritin must not be activated by incoming iron, since this would represent a counterproductive storage during the phase of high iron demand. Recently we have demonstrated that during terminal differentiation primary erythroid cells satisfy their exceptionally high requirements for iron by switching to a mode where the post-transcriptional, iron-dependent regulatory system, formed by iron responsive proteins (IRP1 and IRP2) and iron responsive elements (IREs), seems to sense a low-iron state. This occurs despite a massive net increase of iron import into the cell (Schranzhofer et al., Blood107:4159, 2006). To examine the hypothesis that erythroid cells have low non-heme iron levels in their cytosol, we experimentally increased the cytosolic iron pool by either inhibiting heme biosynthesis or overloading cells with iron. Both block of heme synthesis by either succinylacetone or isonicotinic acid hydrazide (INH) or administration of ferric ammonium citrate, resulted in a clear increase in ferritin levels. This increase was directly proportional to the increase in the cellular concentration of non-heme-iron. Moreover, the effect of INH, the inhibitor of 5-aminolevulinic acid (ALA) synthase, could be reversed by the addition of ALA. Strikingly, increases in ferritin expression upon perturbation of cellular iron homeostasis strongly correlated with the loss of IRE-binding activity of IRP2 but not IRP1, as determined by mobility shift assays. This suggests that IRP2 is the major regulator of ferritin expression in erythroid cells. To further elaborate on this observation, we cultured primary erythroblasts derived from IRP1−/− and IRP2−/− mice (kindly provided by Drs. M. Hentze and B. Galy). In agreement with the published phenotype of microcytic hypochromic anemia, only erythroblasts lacking IRP2 exhibited a reduction in hemoglobinization. Moreover, only IRP2−/− cells showed a significant increase in ferritin expression, whereas developing RBC lacking IRP1 had levels of ferritin protein equal to wild type cells. We conclude that in erythroid cells efficient shuttling of incoming iron towards mitochondria and its prompt use for heme formation is important to keep the cytosol in an iron-deprived state and consequently ferritin protein levels low. This translational repression seems to be mainly achieved by IRP2. Together with the observation that surface expression of TfR was reduced in IRP2−/− erythroblasts during self renewal but not during terminal differentiation, our results suggest that not only down-regulation of TfR, but also up-regulation of ferritin may be a major factor for the anemic phenotype observed in IRP2−/− mice.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».