An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis
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Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of genes responsible for iron uptake, release, use, and storage through the actions of the iron regulatory proteins IRP1 and IRP2. However, the manner in which iron levels are sensed to affect IRP2 activity is poorly understood. We found that an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. These observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.
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Under iron-loaded conditions, IRP2 interacts with FBXL5, which promotes IRP2 ubiquitination via the SKP1-CUL1-RBX1 E3 ubiquitin ligase complex and subsequent degradation.
“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 Salahudeen et al., 2009
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- Authors
- Salahudeen, A. A., Thompson, J. W., Ruiz, J. C., Ma, H.-W., Kinch, L. N., Li, Q., Grishin, N. V., & Bruick, R. K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Salahudeen, Ameen A.
- Thompson, Joel W.
- Bruick, Richard K.
- Venue
- Science
- Published
- 2009-10-30
- Volume
- 326
- Issue
- 5953
- Pages
- 722-726
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3582197
- OpenAlex
- W2043523270
- Cited by
- 432
- References
- 26
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 23 · 2023: 29 · 2022: 24 · 2021: 20 · 2020: 27 · 2019: 24 · 2018: 22 · 2017: 27 · 2016: 12 · 2015: 23 · 2014: 37 · 2013: 32 · 2012: 37
- FWCI
- 18.59
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA115962, R01CA115962)
- National Center for Research Resources (C06RR015437, C06 RR 15437-01))
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- iron homeostasis, FBXL5, E3 ubiquitin ligase, IRP2, iron regulatory proteins, iron sensing, protein stability, proteasomal degradation, oxygen sensing, post-transcriptional regulation
- MeSH terms
- Cell Line, HeLa Cells, Hemerythrin, Homeostasis, Humans, Iron, Oxygen, Recombinant Fusion Proteins, Protein Structure, Tertiary, Catalytic Domain, RNA, Small Interfering, Iron Regulatory Protein 2, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, F-Box Proteins
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