Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor
Open accessAbstract
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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A cross-regulatory loop may exist between HIF and NF-κB pathways and may involve other transcriptional regulators that bear non-redundant PHD sensitivity, including ATF-4 and Notch.
“It also seems that increased NF-κB activity in hypoxia can be regulated by HIF-144, thus a cross-regulatory loop may exist between these two pathways and may involve other transcriptional regulators that bear non-redundant PHD sensitivity, including activating transcription factor-4 and Notch52,53”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [53]
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References 39 · Cited by 214
Research works printed but not linked: 1
- Ivan M, Kondo K, Yang H, et al. HIF␣ targeted for VHL-mediated destruction by proline hydroxyla- tion: implications for O2 sensing. Science. 2001; 292:464-468.
- Authors
- Köditz, J., Nesper, J., Wottawa, M., Stiehl, D. P., Camenisch, G., Franke, C., Myllyharju, J., Wenger, R. H., & Katschinski, D. M.
- Affiliations
- University of Göttingen (DE)
- Martin Luther University Halle-Wittenberg (DE)
- University of Zurich (CH)
- University of Oulu (FI)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-11-15
- Volume
- 110
- Issue
- 10
- Pages
- 3610-3617
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2082064411
- Cited by
- 214
- References
- 39
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 9 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 15 · 2015: 9 · 2014: 18 · 2013: 23 · 2012: 10
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- GRO (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- European Commission (44843)
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (44843, 116047, 3100A0)
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATF4, PHD3, oxygen sensing, protein stability, hypoxia, prolyl 4-hydroxylase, oxygen-dependent degradation domain, endoplasmic reticulum stress, unfolded protein response, VHL, hypoxia-inducible factor, cell fate, dimethyloxalylglycine
- MeSH terms
- Amino Acid Sequence, HeLa Cells, Humans, Molecular Sequence Data, Oxygen, Protein Binding, Protein Processing, Post-Translational, Cell Hypoxia, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Dioxygenases, Activating Transcription Factor 4, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases
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