Erythropoietin signaling regulates heme biosynthesis

Chung, Jacky, Wittig, Johannes Gottfried, 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 and Paw, Barry H (2017) Erythropoietin signaling regulates heme biosynthesis. eLife, 2017 (6). ISSN 2050-084X

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: epo signaling,heme metabolism,porphyria,fech,pka
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science
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Depositing User: Pure Connector
Date Deposited: 02 Jun 2017 05:07
Last Modified: 03 May 2020 23:44
URI: https://ueaeprints.uea.ac.uk/id/eprint/63655
DOI: 10.7554/eLife.24767

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