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Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase
Open accessAbstract
Iron Sensor Intracellular iron is an essential cofactor for many proteins, but can also damage macromolecules, so its levels are carefully controlled. Cellular iron homeostasis is mediated by iron regulatory proteins that regulate the expression of genes involved in iron uptake and storage. However, it is not clear how cells sense iron bioavailability (see the Perspective by Rouault ). Using different approaches, Salahudeen et al. (p. 722 , published online 17 September) and Vashisht et al. (p. 718 , published online 17 September) have identified the F-box protein FBXL5 as a human iron sensor. FBXL5 is part of an E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins and thereby cellular iron levels. It contains a hemerythrin domain that binds iron and acts as an iron-dependent regulatory switch, causing the degradation of FBXL5 under low iron conditions. This alternative pathway for the regulation of iron homeostasis has implications for both normal cellular physiology and disease.
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“Under iron-loaded conditions, IRP2 interacts with FBXL5 (F-box and leucine-rich repeat protein 5) which promotes IRP2 ubiquitination via the SKP1-CUL1-RBX1 E3 ubiquitin ligase complex and subsequent degradation (Salahudeen et al., 2009; Vashisht et al., 2009).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Vashisht et al., 2009
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Metadata
- Authors
- Vashisht, A. A., Zumbrennen, K. B., Huang, X., Powers, D. N., Durazo, A., Sun, D., Bhaskaran, N., Persson, A., Uhlen, M., Sangfelt, O., Spruck, C., Leibold, E. A., & Wohlschlegel, J. A.
- Affiliations
- University of California, Los Angeles (US)
- Departments of Medicine and Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
- Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
- Karolinska University Hospital (SE)
- AlbaNova (SE)
- School of Biotechnology, Department of Proteomics, Royal Institute of Technology/AlbaNova, SE-106 91 Stockholm, Sweden.
- University of Utah (US)
- Corresponding author
- Wohlschlegel, James A.
- ORCID
- Venue
- Science
- Published
- 2009-10-30
- Volume
- 326
- Issue
- 5953
- Pages
- 718-721
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2929180
- OpenAlex
- W1997734311
- Cited by
- 429
- References
- 21
- Citations by year
- 2026: 8 · 2025: 32 · 2024: 23 · 2023: 22 · 2022: 19 · 2021: 27 · 2020: 28 · 2019: 23 · 2018: 21 · 2017: 31 · 2016: 13 · 2015: 23 · 2014: 37 · 2013: 31 · 2012: 41
- FWCI
- 19.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM 45201, R01GM045201, R01GM089778)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- iron homeostasis, FBXL5, E3 ubiquitin ligase, iron regulatory proteins, protein degradation, iron bioavailability
- MeSH terms
- Cell Line, Hemerythrin, Homeostasis, Humans, Iron, Oxygen, Recombinant Proteins, Protein Structure, Tertiary, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, F-Box Proteins, Cullin Proteins, SKP Cullin F-Box Protein Ligases
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