Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling.
Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling.
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DOI：
10.1371/journal.pone.0023850
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Goldfarb AN
中科院分区：
文献类型：
--
作者：
Talbot AL;Bullock GC;Delehanty LL;Sattler M;Zhao ZJ;Goldfarb AN
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. 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. 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.
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影响因子：
3.7
作者：
Galli S;Jahn O;Hitt R;Hesse D;Opitz L;Plessmann U;Urlaub H;Poderoso JJ;Jares-Erijman EA;Jovin TM
通讯作者：
Jovin TM
影响因子：
6.5
作者：
Arcasoy, MO;Jiang, XH
通讯作者：
Jiang, XH
影响因子：
20.3
作者：
Bullock, Grant C.;Delehanty, Lorrie L.;Goldfarb, Adam N.
通讯作者：
Goldfarb, Adam N.
影响因子：
2.6
作者：
Abutin, Randolph M.;Chen, Jingchun;Lung, Tina K.;Lloyd, Joyce A.;Sawyer, Stephen T.;Harada, Hisashi
通讯作者：
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影响因子：
11.2
作者：
Choi, YJ;Elagib, KE;Goldfarb, AN
通讯作者：
Goldfarb, AN