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Irreversible AE1 tyrosine phosphorylation leads to membrane vesiculation in G6PD deficient red cells

Pantaleo, Antonella and Ferru, Emanuela and Carta, Franco and Mannu, Franca and Simula, Luigi Felice and Khadjavi, Amina and Pippia, Proto Gavino and Turrini, Francesco Michelangelo (2011) Irreversible AE1 tyrosine phosphorylation leads to membrane vesiculation in G6PD deficient red cells. PLoS One, Vol. 6 (1), e15847. ISSN 1932-6203. Article.

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DOI: 10.1371/journal.pone.0015847


Background. While G6PD deficiency is one of the major causes of acute hemolytic anemia, the membrane changes leading to red cell lysis have not been extensively studied. New findings concerning the mechanisms of G6PD deficient red cell destruction may facilitate our understanding of the large individual variations in susceptibility to pro-oxidant compounds and aid the prediction of the hemolytic activity of new drugs.
Methodology/Principal Findings. Our results show that treatment of G6PD deficient red cells with diamide (0.25 mM) or divicine (0.5 mM) causes: (1) an increase in the oxidation and tyrosine phosphorylation of AE1; (2) progressive recruitment of phosphorylated AE1 in large membrane complexes which also contain hemichromes; (3) parallel red cell lysis and a massive release of vesicles containing hemichromes. We have observed that inhibition of AE1 phosphorylation by Syk kinase inhibitors prevented its clustering and the membrane vesiculation while increases in AE1 phosphorylation by tyrosine phosphatase inhibitors increased both red cell lysis and vesiculation rates. In control RBCs we observed only transient AE1 phosphorylation.
Conclusions/Significance. Collectively, our findings indicate that persistent tyrosine phosphorylation produces extensive membrane destabilization leading to the loss of vesicles which contain hemichromes. The proposed mechanism of hemolysis may be applied to other hemolytic diseases characterized by the accumulation of hemoglobin denaturation products.

Item Type:Article
ID Code:5386
Uncontrolled Keywords:Glucose-6-phosphate dehydrogenase(G6PD) deficiency, enzymopathy, hemolytic anemia, malaria
Subjects:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Divisions:002 Altri enti e centri di ricerca del Nord Sardegna > Nurex Bioresearch Sassari, Sassari
002 Altri enti e centri di ricerca del Nord Sardegna > Azienda ASL1, Sassari > Ospedale civile SS. Annunziata
001 Università di Sassari > 01 Dipartimenti > Scienze fisiologiche, biochimiche e cellulari
Publisher:Public Library of Science
Copyright Holders:© 2011 Pantaleo et al.
Deposited On:28 Jan 2011 10:29

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