Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome.
Ferritin is a cytosolic molecule comprised of subunits that self-assemble into a nanocage capable of containing up to 4500 iron atoms. Iron stored within ferritin can be mobilized for use within cells or exported from cells. Expression of ferroportin (Fpn) results in export of cytosolic iron and ferritin degradation. Fpn-mediated iron loss from ferritin occurs in the cytosol and precedes ferritin degradation by the proteasome. Depletion of ferritin iron induces the monoubiquitination of ferritin subunits. Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome. Specific mammalian machinery is not required to extract iron from ferritin. Iron can be removed from ferritin when ferritin is expressed in Saccharomyces cerevisiae, which does not have endogenous ferritin. Expressed ferritin is monoubiquitinated and degraded by the proteasome. Exposure of ubiquitination defective mammalian cells to the iron chelator desferrioxamine leads to degradation of ferritin in the lysosome, which can be prevented by inhibitors of autophagy. Thus, ferritin degradation can occur through two different mechanisms.
De Domenico
Ivana
I
Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
Vaughn
Michael B
MB
Li
Liangtao
L
Bagley
Dustin
D
Musci
Giovanni
G
Ward
Diane M
DM
Kaplan
Jerry
J
D027682:Cation Transport Proteins / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D003600:Cytosol / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D000098742:Ferroportin
D027682:Cation Transport Proteins; D007502:Iron Chelating Agents; D014452:Ubiquitins; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron; D046988:Proteasome Endopeptidase Complex; D003676:Deferoxamine