title: Control of iron homeostasis by an iron-regulated ubiquitin ligase.
abstract: Eukaryotic cells require iron for survival and have developed regulatory mechanisms for maintaining appropriate intracellular iron concentrations. The degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathway, but the E3 ubiquitin ligase responsible for its proteolysis has remained elusive. We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. Thus, iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ajay A
authors.initials: AA
authors.lastname: Vashisht
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen
authors.forename: Xinhua
authors.initials: X
authors.lastname: Huang
authors.forename: David N
authors.initials: DN
authors.lastname: Powers
authors.forename: Armando
authors.initials: A
authors.lastname: Durazo
authors.forename: Dahui
authors.initials: D
authors.lastname: Sun
authors.forename: Nimesh
authors.initials: N
authors.lastname: Bhaskaran
authors.forename: Anja
authors.initials: A
authors.lastname: Persson
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
authors.forename: Charles
authors.initials: C
authors.lastname: Spruck
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Leibold
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
mesh_terms: D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism*; D006422:Hemerythrin / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; C521741:FBXL5 protein, human; D006422:Hemerythrin; D011994:Recombinant Proteins; D007501:Iron; D043743:Ubiquitin-Protein Ligase Complexes; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D010100:Oxygen