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

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.

• Authors: Jens Köditz, Jutta Nesper, Marieke Wottawa, Daniel P Stiehl, Gieri Camenisch, Corinna Franke, Johanna Myllyharju, Roland H Wenger, Dörthe M Katschinski
• Journal: Blood (Blood) Vol. 110 Issue 10 Pg. 3610-7 (Nov 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17684156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF4 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Activating Transcription Factor 4
• Dioxygenases
• EGLN3 protein, human
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Oxygen

Topics

• Activating Transcription Factor 4 (chemistry, metabolism)
• Amino Acid Sequence
• Cell Hypoxia (physiology)
• Dioxygenases (chemistry, physiology)
• HeLa Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Molecular Sequence Data
• Oxygen (pharmacology)
• Protein Binding
• Protein Processing, Post-Translational (drug effects)
• Protein Structure, Tertiary
• Sequence Homology, Amino Acid