Pleckstrin-2 is essential for erythropoiesis in β-thalassemic mice, reducing apoptosis and enhancing enucleation

• Published in: Communications biology Vol. 4; no. 1; p. 517
• Main Authors: Feola, Maria, Zamperone, Andrea, Moskop, Daniel, Chen, Huiyong, Casu, Carla, Lama, Dechen, Di Martino, Julie, Djedaini, Mansour, Papa, Luena, Martinez, Marc Ruiz, Choesang, Tenzin, Bravo-Cordero, Jose Javier, MacKay, Matthew, Zumbo, Paul, Brinkman, Nathan, Abrams, Charles S., Rivella, Stefano, Hattangadi, Shilpa, Mason, Christopher E., Hoffman, Ronald, Ji, Peng, Follenzi, Antonia, Ginzburg, Yelena Z.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/44; 13/51; 13/95; 14; 14/10; 14/34; 14/63; 45/61; 631/337; 692/699/1541/13; 82/80; 96/1; 96/2; Animals; Apoptosis; beta-Thalassemia - etiology; beta-Thalassemia - metabolism; beta-Thalassemia - pathology; Biology; Biomedical and Life Sciences; Cell differentiation; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell survival; Cofilin; Drug development; Embryos; Enucleation; Erythroblasts; Erythroblasts - metabolism; Erythroblasts - pathology; Erythropoiesis; Erythropoietin; Female; Lethality; Life Sciences; Localization; Male; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Pleckstrin; Stat5 protein; Thalassemia; Therapeutic applications; Transferrins
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02046-9

Erythropoiesis involves complex interrelated molecular signals influencing cell survival, differentiation, and enucleation. Diseases associated with ineffective erythropoiesis, such as β-thalassemias, exhibit erythroid expansion and defective enucleation. Clear mechanistic determinants of what make erythropoiesis effective are lacking. We previously demonstrated that exogenous transferrin ameliorates ineffective erythropoiesis in β-thalassemic mice. In the current work, we utilize transferrin treatment to elucidate a molecular signature of ineffective erythropoiesis in β-thalassemia. We hypothesize that compensatory mechanisms are required in β-thalassemic erythropoiesis to prevent apoptosis and enhance enucleation. We identify pleckstrin-2—a STAT5-dependent lipid binding protein downstream of erythropoietin—as an important regulatory node. We demonstrate that partial loss of pleckstrin-2 leads to worsening ineffective erythropoiesis and pleckstrin-2 knockout leads to embryonic lethality in β-thalassemic mice. In addition, the membrane-associated active form of pleckstrin-2 occurs at an earlier stage during β-thalassemic erythropoiesis. Furthermore, membrane-associated activated pleckstrin-2 decreases cofilin mitochondrial localization in β-thalassemic erythroblasts and pleckstrin-2 knockdown in vitro induces cofilin-mediated apoptosis in β-thalassemic erythroblasts. Lastly, pleckstrin-2 enhances enucleation by interacting with and activating RacGTPases in β-thalassemic erythroblasts. This data elucidates the important compensatory role of pleckstrin-2 in β-thalassemia and provides support for the development of targeted therapeutics in diseases of ineffective erythropoiesis. Maria Feola et al., elucidate the compensatory role of pleckstrin-2 in ineffective erythropoiesis in β-thalassemic mice by reducing cofilin-mediated apoptosis and enhancing enucleation by activating RacGTPases. These findings could support future therapeutic interventions.