Control of iron homeostasis by an iron-regulated ubiquitin ligase

Vashisht, Ajay A.; Zumbrennen, Kimberly B.; Huang, Xinhua; Powers, David N.; Durazo, Armando; Sun, Dahui; Bhaskaran, Nimesh; Persson, Anja; Uhlen, Mathias; Sangfelt, Olle; Spruck, Charles; Leibold, Elizabeth A.; Wohlschlegel, James A.

doi:10.1126/science.1176333

Cited by 431Iron Metabolism and DisordersUbiquitin and proteasome pathwaysNeurological diseases and metabolism

Control of iron homeostasis by an iron-regulated ubiquitin ligase

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Vashisht, Ajay A., Zumbrennen, Kimberly B., Huang, Xinhua, Powers, David N., Durazo, Armando, Sun, Dahui, Bhaskaran, Nimesh, Persson, Anja +5 more·2009·Science

DOI 10.1126/science.1176333PMC PMC2929180

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Abstract

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, 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 Vashisht et al., 2009

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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: Huang, Xinhua
Powers, David N.
Durazo, Armando
Sun, Dahui
Sangfelt, Olle
Spruck, Charles
Leibold, Elizabeth A.
Wohlschlegel, James A.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2009-10-30
Volume: 326
Issue: 5953
Pages: 718-721
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1176333
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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Control of iron homeostasis by an iron-regulated ubiquitin ligase

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