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Erythropoietin signaling regulates heme biosynthesis

  1. Jacky Chung
  2. Johannes Gottfried Wittig
  3. Alireza Ghamari
  4. Manami Maeda
  5. Tamara A Dailey
  6. Hector Bergonia
  7. Martin D Kafina
  8. Emma E Coughlin
  9. Catherine E Minogue
  10. Alexander S Hebert
  11. Liangtao Li
  12. Jerry Kaplan
  13. Harvey F Lodish
  14. Daniel E Bauer
  15. Stuart H Orkin
  16. Alan B Cantor
  17. Takahiro Maeda
  18. John D Phillips
  19. Joshua J Coon
  20. David J Pagliarini
  21. Harry A Dailey
  22. Barry H Paw  Is a corresponding author
  1. Harvard Medical School, United States
  2. University of East Anglia, United Kingdom
  3. Kyushu University Hospital, Japan
  4. University of Georgia, United States
  5. University of Utah School of Medicine, United States
  6. Genome Center of Wisconsin, United States
  7. University of Wisconsin-Madison, United States
  8. Massachusetts Institute of Technology, United States
Research Article
  • Cited 8
  • Views 1,635
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Cite this article as: eLife 2017;6:e24767 doi: 10.7554/eLife.24767

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

  1. Jacky Chung

    Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Johannes Gottfried Wittig

    School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0598-2897
  3. Alireza Ghamari

    Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Manami Maeda

    Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoko, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Tamara A Dailey

    Department of Microbiology, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hector Bergonia

    Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Martin D Kafina

    Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Emma E Coughlin

    Genome Center of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Catherine E Minogue

    Department of Chemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alexander S Hebert

    Genome Center of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Liangtao Li

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jerry Kaplan

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Harvey F Lodish

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Daniel E Bauer

    Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Stuart H Orkin

    Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Alan B Cantor

    Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Takahiro Maeda

    Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoko, Japan
    Competing interests
    The authors declare that no competing interests exist.
  18. John D Phillips

    Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Joshua J Coon

    Genome Center of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. David J Pagliarini

    Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0001-0087
  21. Harry A Dailey

    Department of Microbiology, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Barry H Paw

    Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    For correspondence
    bpaw@rics.bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0492-1419

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.

Reviewing Editor

  1. David Ginsburg, Howard Hughes Medical Institute, University of Michigan, United States

Publication history

  1. Received: December 30, 2016
  2. Accepted: May 28, 2017
  3. Accepted Manuscript published: May 29, 2017 (version 1)
  4. Version of Record published: June 20, 2017 (version 2)

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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