A novel role for aconitase during erythroid development

Erythropoiesis is the biological process by which red blood cells are produced from multipotent progenitors in the adult bone marrow. Due to their short 120 day lifespan, there is a constant demand for new red cells placed on the marrow. Proliferation, differentiation and survival of erythroid progenitors are tightly controlled by multiple factors, including levels of the hormone erythropoietin (EPO) and iron bioavailability. While abundant data indicate that EPO and iron cooperate to optimize red cell production, the precise mechanisms coupling these two factors remain poorly understood. Prior studies identified the aconitase enzymes as mediators of the erythroid response to iron deficiency. In the current study, a role for aconitase during erythropoiesis was evaluated in iron-replete conditions. Based on a targeted pharmacological approach, results presented here demonstrate that aconitase activity regulates erythroid differentiation. Inhibition of aconitase with fluoroacetate (FA) impaired the proliferation and differentiation of primary human erythroid progenitors, but not viability or total ATP content. In vivo, aconitase inhibition caused a normochromic, normocytic anemia with low reticulocyte counts and elevated serum EPO, but spared other lineages. FA treatment also reduced the red cell mass in a mouse model of erythrocytosis caused by mutant JAK2V617F. A likely mechanism involves disruption of a subset of ERK1/2-mediated signaling events. Activation of the downstream ERK1/2 target RSK was severely diminished under aconitase inhibition, and inhibition of ERK activation recapitulated all the effects of the aconitase inhibitor. Furthermore, aconitase was found to physically interact with ERK1 and ERK2. iii Aconitase may act as a scaffold for ERK1/2 activation and target the kinase to key downstream effectors of the erythroid development program. Interestingly, ERK1 -/- mice were partially resistant to the effects of the aconitase inhibitor, supporting a role for ERK1 in mediating the effects of aconitase inhibition. Taken together, these results support a regulatory role for aconitase in erythropoiesis, possibly as an integrator of EPO and iron-mediated signals. Targeting this pathway may yield novel therapeutic options in several diseases of dysregulated erythroid production.

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