Journal Article

Erythropoietin signaling regulates heme biosynthesis

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

2017

Overview

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. Heme is an iron-containing compound that is important for all living things, from bacteria to humans. Our red blood cells use heme to carry oxygen and deliver it throughout the body. The amount of heme that is produced must be tightly regulated. Too little or too much heme in a person’s red blood cells can lead to blood-related diseases such as anemia and porphyria. Yet, while scientists knew the enzymes needed to make heme, they did not know how these enzymes were controlled. Now, Chung et al . show that an important signaling molecule called erythropoietin controls how much heme is produced when red blood cells are made. The experiments used a combination of red blood cells from humans and mice as well as zebrafish, which are useful model organisms because their blood develops in a similar way to humans. When Chung et al . inhibited components of erythropoietin signaling, heme production was blocked too and the red blood cells could not work properly. These new findings pave the way to look at human patients with blood-related disorders to determine if they have defects in the erythropoietin signaling cascade. In the future, this avenue of research might lead to better treatments for a variety of blood diseases in humans.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: A Kinase Anchor Proteins - metabolism / AKAP / Animal models / Animals / Biochemistry / Biomedical research / Biosynthesis / Cellular signal transduction / Cyclic AMP-Dependent Protein Kinases - metabolism / Danio rerio / Developmental Biology and Stem Cells / Erythropoiesis / Erythropoietin / Erythropoietin - metabolism / Experiments / Ferrochelatase / GATA-1 protein / GATA1 Transcription Factor - metabolism / Hematological diseases / Hematology / Heme / Heme - biosynthesis / Hemoglobin / Hospitals / Human Biology and Medicine / Humans / Intermediates / Intracellular signalling / Kinases / Mass spectrometry / Metabolism / Mice / Mitochondria / Mitochondrial Membranes - metabolism / Mutation / Observations / Phosphorylation / Physiological aspects / PKA / porphyria / Post-translation / Protein kinase A / Proteins / Protocol / Protoporphyrin / Rodents / Scientific imaging / Signal Transduction / Statistical analysis / Transcription / Zebrafish