title: Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling.
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.
  
  
  RESULTS
  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
  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.
authors: Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Anne-Laure
authors: AL
authors: Talbot
authors: Grant C
authors: GC
authors: Bullock
authors: Lorrie L
authors: LL
authors: Delehanty
authors: Martin
authors: M
authors: Sattler
authors: Zhizhuang Joe
authors: ZJ
authors: Zhao
authors: Adam N
authors: AN
authors: Goldfarb
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004920:Erythropoiesis; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D011087:Polycythemia Vera
chemical_list: D004791:Enzyme Inhibitors; D000154:Aconitate Hydratase