Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase

Redox Biology

Iana Iatcenko¹  De Franceschi Lucia²  Marcial Quino Jaime³  Andrea Carpentieri⁴  Piero Pucci⁴  Lupo Francesca⁵  Federti Enrica⁵  Matte’ Alessandro⁵  Cappellini Maria Domenica⁵  Forni Gian Luca⁶  Cesaro Luca⁷  Di Paolo Maria Luisa⁷  Brunati Anna Maria⁷  Tibaldi Elena⁷  Turrini Francesco⁸  Antonella Pantaleo⁹  Soo Young Choi^1,10  Kim Dae Won^1,10  Gomez Manzo Saul^1,11  Xiuli An^1,12 

[1] Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA;Centro Della Microcitemia e Delle Anemie Congenite, Ospedale Galliera, Genova, Italy;Consejo Nacional de Ciencia y Tecnology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico;Dept of Chemical Sciences, University Federico II, Naples, Italy;Dept of Medicine University of Verona and AOUI Verona, Verona, Italy;Dept of Medicine, University of Milan, Milan, Italy;Dept of Molecular Medicine, University of Padua, Padua, Italy;Dept of Oncology, University of Torino, Torino, Italy;Dept of Physiology, University of Sassari, Sassari, Italy;Institute of Bioscience and Biotechnology, Hallym University, Gangowo-do, South Korea;Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico;School of Life Sciences, Zhengzhou University, Zhengzhou, China;

关键词: Red cells;    Primaquine;    G6PD;    Oxidation;    Signaling;   

DOI  :  

来源: DOAJ

【 摘 要 】

Fyn is a tyrosine kinase belonging to the Src family (Src-Family-Kinase, SFK), ubiquitously expressed. Previously, we report that Fyn is important in stress erythropoiesis. Here, we show that in red cells Fyn specifically stimulates G6PD activity, resulting in a 3-fold increase enzyme catalytic activity (kcat) by phosphorylating tyrosine (Tyr)-401. We found Tyr-401 on G6PD as functional target of Fyn in normal human red blood cells (RBC), being undetectable in G6PD deficient RBCs (G6PD-Mediterranean and G6PD-Genova). Indeed, Tyr-401 is located to a region of the G6PD molecule critical for the formation of the enzymatically active dimer. Amino acid replacements in this region are mostly associated with a chronic hemolysis phenotype. Using mutagenesis approach, we demonstrated that the phosphorylation status of Tyr401 modulates the interaction of G6PD with G6P and stabilizes G6PD in a catalytically more efficient conformation. RBCs from Fyn-/−mice are defective in G6PD activity, resulting in increased susceptibility to primaquine-induced intravascular hemolysis. This negatively affected the recycling of reduced Prx2 in response to oxidative stress, indicating that defective G6PD phosphorylation impairs defense against oxidation. In human RBCs, we confirm the involvement of the thioredoxin/Prx2 system in the increase vulnerability of G6PD deficient RBCs to oxidation. In conclusion, our data suggest that Fyn is an oxidative radical sensor, and that Fyn-mediated Tyr-401 phosphorylation, by increasing G6PD activity, plays an important role in the physiology of RBCs. Failure of G6PD activation by this mechanism may be a major limiting factor in the ability of G6PD deficient RBCs to withstand oxidative stress.

【 授权许可】

Unknown