Control of iron homeostasis by an iron-regulated ubiquitin ligase.
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.
Vashisht
Ajay A
AA
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Zumbrennen
Kimberly B
KB
Huang
Xinhua
X
Powers
David N
DN
Durazo
Armando
A
Sun
Dahui
D
Bhaskaran
Nimesh
N
Persson
Anja
A
Uhlen
Mathias
M
Sangfelt
Olle
O
Spruck
Charles
C
Leibold
Elizabeth A
EA
Wohlschlegel
James A
JA
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*
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