Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase
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 acti...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720308442 |
| _version_ | 1818483469224771584 |
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| author | Matte’ Alessandro Lupo Francesca Tibaldi Elena Di Paolo Maria Luisa Federti Enrica Andrea Carpentieri Piero Pucci Brunati Anna Maria Cesaro Luca Turrini Francesco Gomez Manzo Saul Soo Young Choi Marcial Quino Jaime Kim Dae Won Antonella Pantaleo Xiuli An Iana Iatcenko Cappellini Maria Domenica Forni Gian Luca De Franceschi Lucia |
| author_facet | Matte’ Alessandro Lupo Francesca Tibaldi Elena Di Paolo Maria Luisa Federti Enrica Andrea Carpentieri Piero Pucci Brunati Anna Maria Cesaro Luca Turrini Francesco Gomez Manzo Saul Soo Young Choi Marcial Quino Jaime Kim Dae Won Antonella Pantaleo Xiuli An Iana Iatcenko Cappellini Maria Domenica Forni Gian Luca De Franceschi Lucia |
| author_sort | Matte’ Alessandro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T15:42:23Z |
| format | Article |
| id | doaj.art-b335f146753f4b91a8e2920c6f591ab6 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T15:42:23Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-b335f146753f4b91a8e2920c6f591ab62022-12-22T01:43:04ZengElsevierRedox Biology2213-23172020-09-0136101639Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenaseMatte’ Alessandro0Lupo Francesca1Tibaldi Elena2Di Paolo Maria Luisa3Federti Enrica4Andrea Carpentieri5Piero Pucci6Brunati Anna Maria7Cesaro Luca8Turrini Francesco9Gomez Manzo Saul10Soo Young Choi11Marcial Quino Jaime12Kim Dae Won13Antonella Pantaleo14Xiuli An15Iana Iatcenko16Cappellini Maria Domenica17Forni Gian Luca18De Franceschi Lucia19Dept of Medicine University of Verona and AOUI Verona, Verona, ItalyDept of Medicine University of Verona and AOUI Verona, Verona, ItalyDept of Molecular Medicine, University of Padua, Padua, ItalyDept of Molecular Medicine, University of Padua, Padua, ItalyDept of Medicine University of Verona and AOUI Verona, Verona, ItalyDept of Chemical Sciences, University Federico II, Naples, ItalyDept of Chemical Sciences, University Federico II, Naples, ItalyDept of Molecular Medicine, University of Padua, Padua, ItalyDept of Molecular Medicine, University of Padua, Padua, ItalyDept of Oncology, University of Torino, Torino, ItalyLaboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, MexicoInstitute of Bioscience and Biotechnology, Hallym University, Gangowo-do, South KoreaConsejo Nacional de Ciencia y Tecnology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, MexicoInstitute of Bioscience and Biotechnology, Hallym University, Gangowo-do, South KoreaDept of Physiology, University of Sassari, Sassari, ItalySchool of Life Sciences, Zhengzhou University, Zhengzhou, China; Laboratory of Membrane Biology, New York Blood Center, New York, NY, USADept of Medicine University of Verona and AOUI Verona, Verona, ItalyDept of Medicine, University of Milan, Milan, ItalyCentro Della Microcitemia e Delle Anemie Congenite, Ospedale Galliera, Genova, ItalyDept of Medicine University of Verona and AOUI Verona, Verona, Italy; Corresponding author. Dept of Medicine, University of Verona and AOUI Verona, P.Le L. Scuro, 10, 37134, Verona, Italy.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.http://www.sciencedirect.com/science/article/pii/S2213231720308442Red cellsPrimaquineG6PDOxidationSignaling |
| spellingShingle | Matte’ Alessandro Lupo Francesca Tibaldi Elena Di Paolo Maria Luisa Federti Enrica Andrea Carpentieri Piero Pucci Brunati Anna Maria Cesaro Luca Turrini Francesco Gomez Manzo Saul Soo Young Choi Marcial Quino Jaime Kim Dae Won Antonella Pantaleo Xiuli An Iana Iatcenko Cappellini Maria Domenica Forni Gian Luca De Franceschi Lucia Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase Redox Biology Red cells Primaquine G6PD Oxidation Signaling |
| title | Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase |
| title_full | Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase |
| title_fullStr | Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase |
| title_full_unstemmed | Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase |
| title_short | Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase |
| title_sort | fyn specifically regulates the activity of red cell glucose 6 phosphate dehydrogenase |
| topic | Red cells Primaquine G6PD Oxidation Signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720308442 |
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