PUBLICATION
Erythropoietin signaling regulates heme biosynthesis
- Authors
- Chung, J., Wittig, J.G., Ghamari, A., Maeda, M., Dailey, T.A., Bergonia, H., Kafina, M.D., Coughlin, E.E., Minogue, C.E., Hebert, A.S., Li, L., Kaplan, J., Lodish, H.F., Bauer, D.E., Orkin, S.H., Cantor, A.B., Maeda, T., Phillips, J.D., Coon, J.J., Pagliarini, D.J., Dailey, H.A., Paw, B.H.
- ID
- ZDB-PUB-170531-15
- Date
- 2017
- Source
- eLIFE 6: (Journal)
- Registered Authors
- Paw, Barry, Wittig, Johannes
- Keywords
- developmental biology, human biology, medicine, mouse, stem cells
- MeSH Terms
-
- GATA1 Transcription Factor/metabolism*
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Signal Transduction*
- A Kinase Anchor Proteins/metabolism*
- Zebrafish
- Mice
- Animals
- Erythropoietin/metabolism*
- Mitochondrial Membranes/metabolism
- Heme/biosynthesis*
- Humans
- PubMed
- 28553927 Full text @ Elife
Citation
Chung, J., Wittig, J.G., Ghamari, A., Maeda, M., Dailey, T.A., Bergonia, H., Kafina, M.D., Coughlin, E.E., Minogue, C.E., Hebert, A.S., Li, L., Kaplan, J., Lodish, H.F., Bauer, D.E., Orkin, S.H., Cantor, A.B., Maeda, T., Phillips, J.D., Coon, J.J., Pagliarini, D.J., Dailey, H.A., Paw, B.H. (2017) Erythropoietin signaling regulates heme biosynthesis. eLIFE. 6.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping