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 Blood, 15 November 2007, Vol. 110, No. 10, pp. 3610-3617.
Prepublished online as a Blood First Edition Paper on August 7, 2007; DOI 10.1182/blood-2007-06-094441.

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HEMATOPOIESIS

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

Jens Köditz1, Jutta Nesper2, Marieke Wottawa1, Daniel P. Stiehl3, Gieri Camenisch3, Corinna Franke2, Johanna Myllyharju4, Roland H. Wenger3, and Dörthe M. Katschinski1

1 Department of Heart and Circulatory Physiology, Center of Physiology and Pathophysiology, Georg-August University Göttingen, Göttingen, Germany; 2 Cell Physiology Group, Medical Faculty, Martin-Luther University Halle, Halle, Germany; 3 Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; and 4 Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

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.


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Related Article in Blood Online:

A wrinkle in the unfolding of hypoxic response: HIF and ATF4
Alexander Weidemann and Randall S. Johnson
Blood 2007 110: 3492-3493. [Full Text] [PDF]





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