E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis

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 p...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2009-10, Vol.326 (5953), p.722-726
Main Authors: Salahudeen, Ameen A, Thompson, Joel W, Ruiz, Julio C, Ma, He-Wen, Kinch, Lisa N, Li, Qiming, Grishin, Nick V, Bruick, Richard K
Format: Article
Language:English
Subjects:
Biochemistry
Biological and medical sciences
Catalytic Domain
Cell Line
Cell lines
Cell physiology
Cellular biology
F-Box Proteins - chemistry
F-Box Proteins - metabolism
Fundamental and applied biological sciences. Psychology
Gene expression
HEK293 cells
HeLa Cells
Hemerythrin - metabolism
Homeostasis
Humans
Iron
Iron - metabolism
Iron Regulatory Protein 2 - metabolism
Messenger RNA
Miscellaneous
Molecular and cellular biology
Oxygen - metabolism
Physiological regulation
Protein Structure, Tertiary
Proteins
Recombinant Fusion Proteins - metabolism
RNA, Small Interfering
Small interfering RNA
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Ubiquitins
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1176326