Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH)
Open accessAbstract
Studies on hypoxia-sensitive pathways have revealed a series of Fe(II)-dependent dioxygenases that regulate hypoxia-inducible factor (HIF) by prolyl and asparaginyl hydroxylation. The recognition of these unprecedented signaling processes has led to a search for other substrates of the HIF hydroxylases. Here we show that the human HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also efficiently hydroxylates specific asparaginyl (Asn)-residues within proteins of the IκB family. After the identification of a series of ankyrin repeat domain (ARD)-containing proteins in a screen for proteins interacting with FIH, the ARDs of p105 ( NFKB1 ) and IκBα were shown to be efficiently hydroxylated by FIH at specific Asn residues in the hairpin loops linking particular ankyrin repeats. The target Asn residue is highly conserved as part of the ankyrin consensus, and peptides derived from a diverse range of ARD-containing proteins supported FIH enzyme activity. These findings demonstrate that this type of protein hydroxylation is not restricted to HIF and strongly suggest that FIH-dependent ARD hydroxylation is a common occurrence, potentially providing an oxygen-sensitive signal to a diverse range of processes.
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- Authors
- Cockman, M. E., Lancaster, D. E., Stolze, I. P., Hewitson, K. S., McDonough, M. A., Coleman, M. L., Coles, C. H., Yu, X., Hay, R. T., Ley, S. C., Pugh, C. W., Oldham, N. J., Masson, N., Schofield, C. J., & Ratcliffe, P. J.
- Affiliations
- University of Oxford (GB)
- Centre for Ecology and Hydrology, Oxford OX1 3SR, United Kingdom;
- University of Dundee (GB)
- National Institute for Medical Research (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-10-03
- Volume
- 103
- Issue
- 40
- Pages
- 14767-14772
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1578504
- OpenAlex
- W2066077682
- Cited by
- 285
- References
- 22
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 8 · 2020: 13 · 2019: 10 · 2018: 8 · 2017: 14 · 2016: 13 · 2015: 15 · 2014: 12 · 2013: 15 · 2012: 18
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council (B18672, BBS/B/07683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- factor inhibiting HIF, FIH, ankyrin repeats, IκB proteins, IκBα, hypoxia signaling, post-translational modification, oxygen sensing
- MeSH terms
- NF-KappaB Inhibitor alpha, Amino Acid Sequence, Decarboxylation, Humans, Mixed Function Oxygenases, Hydroxylation, Ketoglutaric Acids, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Recombinant Proteins, Repressor Proteins, Mass Spectrometry, Transcription Factors, Ankyrin Repeat, I-kappa B Proteins, Hypoxia-Inducible Factor 1, NF-kappa B p50 Subunit
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