Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system.
Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form. A glycosylphosphatidylinositol (GPI)-anchored form of this enzyme is expressed by astrocytes in the mammalian central nervous system, whereas the secreted form is expressed by the liver and found in serum. Lack of this enzyme results in iron accumulation in the brain and neurodegeneration. Herein, we show using astrocytes purified from the central nervous system of Cp-null mice that GPI-Cp is essential for iron efflux and not involved in regulating iron influx. We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1. In addition, IREG1 alone is unable to efflux iron from astrocytes in the absence of GPI-Cp or secreted Cp. We also provide evidence that the divalent metal influx transporter DMT1 is expressed by astrocytes and is likely to mediate iron influx into these glial cells. The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration.
Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital Research Institute, Montreal, Quebec H3G 1A4, Canada.
Suh Young
SY
Jeong
Samuel
S
David
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D001483:Base Sequence; D001693:Biological Transport, Active; D001921:Brain / Q000166:cytology / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002570:Ceruloplasmin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D038181:FMN Reductase / Q000235:genetics / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D004247:DNA; D038181:FMN Reductase; D017261:Glycosylphosphatidylinositols; D007501:Iron; D033862:Iron-Binding Proteins; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C023903:ferric citrate iron reductase