An oxygen-dependent interaction between FBXL5 and the CIA-Targeting Complex Regulates Iron Homeostasis
Open accessAbstract
The iron-sensing protein FBXL5 is the substrate adaptor for a SKP1-CUL1-RBX1 E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins (IRPs). Here, we describe a mechanism of FBXL5 regulation involving its interaction with the cytosolic Fe-S cluster assembly (CIA) targeting complex composed of MMS19, FAM96B, and CIAO1. We demonstrate that the CIA-targeting complex promotes the ability of FBXL5 to degrade IRPs. In addition, the FBXL5-CIA-targeting complex interaction is regulated by oxygen (O 2) tension displaying a robust association in 21% O 2 that is severely diminished in 1% O 2 and contributes to O 2-dependent regulation of IRP degradation. Together, these data identify a novel oxygen-dependent signaling axis that links IRP-dependent iron homeostasis with the Fe-S cluster assembly machinery.
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Under low oxygen hypoxic conditions, an allosteric-induced stabilizing interaction between FBXL5 and the cytoplasmic Fe-S cluster biogenesis complex CIA is disrupted, leading to enhanced FBXL5 instability and increased IRP2 levels.
“Under low oxygen hypoxic conditions, an allosteric-induced stabilizing interaction between FBXL5 and the cytoplasmic Fe-S cluster biogenesis complex CIA is disrupted leading to enhanced FBXL5 instability and increased IRP2 levels, highlighting again the extensive crosstalk between iron regulation and other important processes such as oxygen sensing (Mayank et al., 2019).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Mayank et al., 2019
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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
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- Authors
- Mayank, A. K., Pandey, V., Vashisht, A. A., Barshop, W. D., Rayatpisheh, S., Sharma, T., Haque, T., Powers, D. N., & Wohlschlegel, J. A.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Wohlschlegel, James A.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 75
- Issue
- 2
- Pages
- 382-393.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6660392
- OpenAlex
- W2950143616
- Cited by
- 45
- References
- 31
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 1
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (GM089778, GM112763, GM007185)
- 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
- FBXL5, iron regulatory proteins, iron homeostasis, oxygen sensing, MMS19, protein degradation, iron-sulfur cluster assembly, hypoxia
- MeSH terms
- HeLa Cells, Homeostasis, Humans, Iron, Iron-Sulfur Proteins, Oxygen, Transcription Factors, Cell Cycle Proteins, Molecular Chaperones, Iron-Regulatory Proteins, Ubiquitin-Protein Ligase Complexes, F-Box Proteins, Multiprotein Complexes, Proteolysis
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