TY - JOUR
T1 - Erythrocytic ferroportin reduces intracellular iron accumulation, hemolysis, and malaria risk
AU - Zhang, De Liang
AU - Wu, Jian
AU - Shah, Binal N.
AU - Greutélaers, Katja C.
AU - Ghosh, Manik C.
AU - Ollivierre, Hayden
AU - Su, Xin Zhuan
AU - Thuma, Philip E.
AU - Bedu-Addo, George
AU - Mockenhaupt, Frank P.
AU - Gordeuk, Victor R.
AU - Rouault, Tracey A.
N1 - Publisher Copyright:
© The Authors, some rights reserved;.
PY - 2018/3/30
Y1 - 2018/3/30
N2 - Malaria parasites invade red blood cells (RBCs), consume copious amounts of hemoglobin, and severely disrupt iron regulation in humans. Anemia often accompanies malaria disease; however, iron supplementation therapy inexplicably exacerbates malarial infections. Here we found that the iron exporter ferroportin (FPN) was highly abundant in RBCs, and iron supplementation suppressed its activity. Conditional deletion of the Fpn gene in erythroid cells resulted in accumulation of excess intracellular iron, cellular damage, hemolysis, and increased fatality in malaria-infected mice. In humans, a prevalent FPN mutation, Q248H (glutamine to histidine at position 248), prevented hepcidin-induced degradation of FPN and protected against severe malaria disease. FPN Q248H appears to have been positively selected in African populations in response to the impact of malaria disease. Thus, FPN protects RBCs against oxidative stress and malaria infection.
AB - Malaria parasites invade red blood cells (RBCs), consume copious amounts of hemoglobin, and severely disrupt iron regulation in humans. Anemia often accompanies malaria disease; however, iron supplementation therapy inexplicably exacerbates malarial infections. Here we found that the iron exporter ferroportin (FPN) was highly abundant in RBCs, and iron supplementation suppressed its activity. Conditional deletion of the Fpn gene in erythroid cells resulted in accumulation of excess intracellular iron, cellular damage, hemolysis, and increased fatality in malaria-infected mice. In humans, a prevalent FPN mutation, Q248H (glutamine to histidine at position 248), prevented hepcidin-induced degradation of FPN and protected against severe malaria disease. FPN Q248H appears to have been positively selected in African populations in response to the impact of malaria disease. Thus, FPN protects RBCs against oxidative stress and malaria infection.
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U2 - 10.1126/science.aal2022
DO - 10.1126/science.aal2022
M3 - Article
C2 - 29599243
AN - SCOPUS:85044621917
VL - 359
SP - 1520
EP - 1523
JO - Science
JF - Science
SN - 0036-8075
IS - 6383
ER -