Erythropoietin signaling regulates heme biosynthesis
- Harvard Medical School, United States
- University of East Anglia, United Kingdom
- Kyushu University Hospital, Japan
- University of Georgia, United States
- University of Utah School of Medicine, United States
- Genome Center of Wisconsin, United States
- University of Wisconsin-Madison, United States
- Massachusetts Institute of Technology, United States
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.
Article and author information
Author details
Johannes Gottfried Wittig
David J Pagliarini
Funding
National Heart, Lung, and Blood Institute (P01 HL032262)
- Barry H Paw
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK096501)
- Harry A Dailey
American Society of Hematology
- Daniel E Bauer
National Heart, Lung, and Blood Institute (P01 HL032262)
- Harvey F Lodish
- Daniel E Bauer
- Stuart H Orkin
- Alan B Cantor
National Institutes of Health (R01 GM115591)
- David J Pagliarini
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK098672)
- David J Pagliarini
National Institutes of Health (P41 GM108538)
- Joshua J Coon
National Institute of Diabetes and Digestive and Kidney Diseases (U54 DK110858)
- John D Phillips
Diamond Blackfan Anemia Foundation
- Barry H Paw
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK070838)
- Barry H Paw
American Cancer Society (RSG-13-379-01-LIB)
- Takahiro Maeda
American Society of Hematology
- Jacky Chung
Canadian Institutes of Health Research
- Jacky Chung
National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK093705)
- Daniel E Bauer
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK052380)
- Jerry Kaplan
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090257)
- John D Phillips
National Institutes of Health (R01 GM114122)
- Joshua J Coon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: In full compliance with BWH IACUC A4752-01 (Protocol #2016N000117) and BCH IACUC Protocol #15-07-2974R.
Copyright
© 2017, Chung et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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