Erythropoietin signaling regulates heme biosynthesis
Author(s)Chung, Jacky; Wittig, Johannes G; Ghamari, Alireza; Maeda, Manami; Dailey, Tamara A; Bergonia, Hector; Kafina, Martin D; Coughlin, Emma E; Minogue, Catherine E; Hebert, Alexander S; Li, Liangtao; Kaplan, Jerry; Lodish, Harvey F; Bauer, Daniel E; Orkin, Stuart H; Cantor, Alan B; Maeda, Takahiro; Phillips, John D; Coon, Joshua J; Pagliarini, David J; Dailey, Harry A; Paw, Barry H; ... Show more Show less
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Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
eLife Sciences Publications, Ltd
Chung, Jacky et al. “Erythropoietin Signaling Regulates Heme Biosynthesis.” eLife 2017, 6 (May 2017): e24767 © 2017 eLife Sciences Publications Ltd
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