Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A
| Autor: | Pedro Gonzalez-Menendez, Ira Phadke, Meagan E Olive, Axel Joly, Julien Papoin, Hongxia Yan, Jérémy Galtier, Jessica Platon, Sun Woo Sophie Kang, Kathy L. McGraw, Marie Daumur, Marie Pouzolles, Taisuke Kondo, Stéphanie Boireau, Franciane Paul, David J Young, Sylvain Lamure, Raghavendra G Mirmira, Anu Narla, Guillaume Cartron, Cynthia E. Dunbar, Myriam Boyer-Clavel, Natalie Porat-Shliom, Valerie Dardalhon, Valerie S Zimmermann, Marc Sitbon, Thomas Dever, Narla Mohandas, Lydie M Da Costa, Namrata D. Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Blood. |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors--by inhibition of deoxyhypusine synthase--abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation. |
| Databáze: | OpenAIRE |
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