Journal article
Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling
PloS one, Vol.6(8), pp.e23850-e23850
08/22/2011
DOI: 10.1371/journal.pone.0023850
PMCID: PMC3161794
PMID: 21887333
Abstract
Background: Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.
Methodology/Principal Findings: In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.
Conclusions/Significance: Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera.
Details
- Title: Subtitle
- Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling
- Creators
- Anne-Laure Talbot - University of VirginiaGrant C. Bullock - University of VirginiaLorrie L. Delehanty - University of VirginiaMartin Sattler - Harvard UniversityZhizhuang Joe Zhao - University of Oklahoma Health Sciences CenterAdam N. Goldfarb - University of Virginia
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.6(8), pp.e23850-e23850
- Publisher
- Public Library Science
- DOI
- 10.1371/journal.pone.0023850
- PMID
- 21887333
- PMCID
- PMC3161794
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Number of pages
- 14
- Grant note
- K08HL093355 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) University of Virginia R01DK079924 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) T32GM007267 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01CA134660 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 2T32GM007267-32; CA134660 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA F32 HL0860046 / Ruth L. Kirschstein National Research Service Award; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 DK079924 / NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Roche Foundation for Anemia Research
- Language
- English
- Date published
- 08/22/2011
- Academic Unit
- Pathology
- Record Identifier
- 9984697738602771
Metrics
11 Record Views