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Article Dans Une Revue Blood Année : 2023

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A

Pedro Gonzalez-Menendez
Ira Phadke
Meagan Olive
Axel Joly
  • Fonction : Auteur
Hongxia Yan
Jérémy Galtier
  • Fonction : Auteur
Sun Woo Sophie Kang
  • Fonction : Auteur
Kathy Mcgraw
  • Fonction : Auteur
Taisuke Kondo
Franciane Paul
  • Fonction : Auteur
David Young
Raghavendra Mirmira
Anu Narla
Guillaume Cartron
Cynthia Dunbar
  • Fonction : Auteur
Myriam Boyer-Clavel
  • Fonction : Auteur
Natalie Porat-Shliom
Valerie Dardalhon
  • Fonction : Auteur
Valerie Zimmermann
  • Fonction : Auteur
Marc Sitbon
Thomas Dever
  • Fonction : Auteur
Narla Mohandas
Lydie Da Costa
Namrata Udeshi
  • Fonction : Auteur
Lionel Blanc
Sandrina Kinet
  • Fonction : Auteur
Naomi Taylor

Résumé

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.
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Dates et versions

hal-03986199 , version 1 (13-02-2023)

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Pedro Gonzalez-Menendez, Ira Phadke, Meagan Olive, Axel Joly, Julien Papoin, et al.. Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A. Blood, 2023, ⟨10.1182/blood.2022017584⟩. ⟨hal-03986199⟩
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