Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A

作者：Pedro González‐Menéndez, 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, Valérie Dardalhon, Valérie S. Zimmermann, Marc Sitbon, Thomas Dever, Narla Mohandas, Lydie Da Costa, Namrata D. Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor · 发表于：Blood · 年份：2023 · DOI：10.1182/blood.2022017584 · 被引用次数：32 · 研究领域：Polyamine Metabolism and Applications、Amino Acid Enzymes and Metabolism、Epigenetics and DNA Methylation

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/cationic amino acid transporter 1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via the activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a posttranslational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors, by the 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 affected 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 (RPs) were especially sensitive to the loss of hypusine, and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in chromosome 5q deletions in myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A....