Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.
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.
Köditz
Jens
J
Department of Heart and Circulatory Physiology, Center of Physiology and Pathophysiology, Georg-August University Göttingen, Göttingen, Germany.
Nesper
Jutta
J
Wottawa
Marieke
M
Stiehl
Daniel P
DP
Camenisch
Gieri
G
Franke
Corinna
C
Myllyharju
Johanna
J
Wenger
Roland H
RH
Katschinski
Dörthe M
DM
D051701:Activating Transcription Factor 4 / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D015687:Cell Hypoxia / Q000502:physiology; D049308:Dioxygenases / Q000737:chemistry / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008969:Molecular Sequence Data; D010100:Oxygen / Q000494:pharmacology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
C497109:ATF4 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051701:Activating Transcription Factor 4; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen