Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Alireza Ghamari
Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, United States
Manami Maeda
Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Tamara A Dailey
Department of Microbiology, University of Georgia, Athens, United States; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States
Hector Bergonia
Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States
Martin D Kafina
Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Emma E Coughlin
Genome Center of Wisconsin, Madison, United States
Catherine E Minogue
Department of Chemistry, University of Wisconsin-Madison, Madison, United States
Alexander S Hebert
Genome Center of Wisconsin, Madison, United States
Liangtao Li
Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
Jerry Kaplan
Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
Harvey F Lodish
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
Daniel E Bauer
Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Stuart H Orkin
Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Alan B Cantor
Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Takahiro Maeda
Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
John D Phillips
Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States
Joshua J Coon
Genome Center of Wisconsin, Madison, United States; Department of Chemistry, University of Wisconsin-Madison, Madison, United States; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, United States
Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
Harry A Dailey
Department of Microbiology, University of Georgia, Athens, United States; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States
Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
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.
