Erythropoietin signaling regulates heme biosynthesis

Jacky Chung, Johannes Gottfried Wittig, Alireza Ghamari, Manami Maeda, Tamara A Dailey, Hector Bergonia, Martin D Kafina, Emma E Coughlin, Catherine E Minogue, Alexander S Hebert, Liangtao Li, Jerry Kaplan, Harvey F Lodish, Daniel E Bauer, Stuart H Orkin, Alan B Cantor, Takahiro Maeda, John D Phillips, Joshua J Coon, David J PagliariniHarry A Dailey, Barry H Paw

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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.
Original languageEnglish
Article numbere24767
JournaleLife
Volume2017
Issue number6
DOIs
Publication statusPublished - 29 May 2017

Keywords

  • EPO signaling
  • heme metabolism
  • porphyria
  • FECH
  • PKA

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