Blood Journal
Leading the way in experimental and clinical research in hematology

Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor

  1. Jens Köditz1,
  2. Jutta Nesper2,
  3. Marieke Wottawa1,
  4. Daniel P. Stiehl3,
  5. Gieri Camenisch3,
  6. Corinna Franke2,
  7. Johanna Myllyharju4,
  8. Roland H. Wenger3, and
  9. Dörthe M. Katschinski1
  1. 1Department of Heart and Circulatory Physiology, Center of Physiology and Pathophysiology, Georg-August University Göttingen, Göttingen, Germany;
  2. 2Cell Physiology Group, Medical Faculty, Martin-Luther University Halle, Halle, Germany;
  3. 3Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; and
  4. 4Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

Abstract

The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following endoplasmic reticulum (ER) stress, and is a critical regulator of cell fate. Here, we identified the zipper II domain of ATF-4 to interact with the oxygen sensor prolyl-4-hydroxylase domain 3 (PHD3). The PHD inhibitors dimethyloxalylglycine (DMOG) and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability, but was independent of the ubiquitin ligase von Hippel–Lindau protein (pVHL). A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of 5 prolyl residues within this ODD domain or siRNA-mediated down-regulation of PHD3, but not of PHD2, was sufficient to stabilize ATF-4 under normoxic conditions. These data demonstrate that PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems, and hence not only confers adaptive responses but also cell fate decisions.

  • Submitted June 7, 2007.
  • Accepted August 6, 2007.
View Full Text