The iron chaperone poly(rC)-binding protein 1 regulates iron efflux through intestinal ferroportin in mice

Abstract Iron is an essential nutrient required by all cells but used primarily for red blood cell production. Because humans have no effective mechanism for ridding the body of excess iron, the absorption of dietary iron must be precisely regulated. The critical site of regulation is the transfer of iron from the absorptive enterocyte to the portal circulation via the sole iron efflux transporter, ferroportin. Here, we report that poly(rC)-binding protein 1 (PCBP1), the major cytosolic iron chaperone, is necessary for the regulation of iron flux through ferroportin in the intestine of mice. Mice lacking PCBP1 in the intestinal epithelium exhibit low levels of enterocyte iron, poor retention of dietary iron in enterocyte ferritin, and excess efflux of iron through ferroportin. Excess iron efflux occurred despite lower levels of ferroportin protein in enterocytes and upregulation of the iron regulatory hormone hepcidin. PCBP1 deletion and the resulting unregulated dietary iron absorption led to poor growth, severe anemia on a low-iron diet, and liver oxidative stress with iron loading on a high-iron diet. Ex vivo culture of PCBP1-depleted enteroids demonstrated no defects in hepcidin-mediated ferroportin turnover. However, measurement of kinetically labile iron pools in enteroids competent or blocked for iron efflux indicated that PCBP1 functioned to bind and retain cytosolic iron and limit its availability for ferroportin-mediated efflux. Thus, PCBP1 coordinates enterocyte iron and reduces the concentration of unchaperoned “free” iron to a low level that is necessary for hepcidin-mediated regulation of ferroportin activity.