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of the Shanghai Key Laboratory of Embryo Original Diseases","award":["31870871"],"award-info":[{"award-number":["31870871"]}]},{"name":"Opening Project of the Shanghai Key Laboratory of Embryo Original Diseases","award":["32070901"],"award-info":[{"award-number":["32070901"]}]},{"name":"Opening Project of the Shanghai Key Laboratory of Embryo Original Diseases","award":["22XD1423900"],"award-info":[{"award-number":["22XD1423900"]}]},{"name":"Opening Project of the Shanghai Key Laboratory of Embryo Original Diseases","award":["shelab202304"],"award-info":[{"award-number":["shelab202304"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we reveal that erythroid cells exhibit an extraordinarily high demand for protein synthesis, which is required for their differentiation but also implies the need for tight regulation to prevent excessive erythropoiesis. Notably, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts as a molecular brake to limit unchecked erythropoiesis. This is evidenced by elevated red blood cell counts in peripheral blood and increased incidence of blood hyperviscosity and thrombosis in eEF2_T56M mice, which are deficient in eEF2 phosphorylation. Mechanistic studies demonstrate that eEF2 phosphorylation selectively regulates the translation of a subset of proteins, including NFE2, which partially mediates the effects of eEF2 modification. Collectively, our findings highlight a previously unappreciated role for translational control in achieving efficient and balanced erythropoiesis, with eEF2 phosphorylation serving as a critical protective mechanism against hyperactive erythropoiesis and offering a potential therapeutic target for hematologic disorders such as polycythemia vera.<\/jats:p>","DOI":"10.3390\/ijms26104801","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T07:34:03Z","timestamp":1747640043000},"page":"4801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Coordinated Translational Control Mediated by eEF2 Phosphorylation Safeguards Erythroid Differentiation"],"prefix":"10.3390","volume":"26","author":[{"given":"Yao","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haozhuo","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanying","family":"Feng","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5277-4321","authenticated-orcid":false,"given":"Cuiping","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5482-1109","authenticated-orcid":false,"given":"Zhiduo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"},{"name":"State Key Laboratory of Systems Medicine for Cancer, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1182\/blood.2021011044","article-title":"Molecular and cellular mechanisms that regulate human erythropoiesis","volume":"139","author":"Caulier","year":"2022","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/ejh.14028","article-title":"Molecular regulatory mechanisms of erythropoiesis and related diseases","volume":"111","author":"Zhu","year":"2023","journal-title":"Eur. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/ajh.27002","article-title":"Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management","volume":"98","author":"Tefferi","year":"2023","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/MOH.0000000000000808","article-title":"Signaling networks guiding erythropoiesis","volume":"31","author":"Kuttikrishnan","year":"2024","journal-title":"Curr. Opin. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6258","DOI":"10.1182\/blood-2011-07-356006","article-title":"From stem cell to red cell: Regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications","volume":"118","author":"Hattangadi","year":"2011","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1182\/blood-2009-10-178129","article-title":"Ribosomopathies: Human disorders of ribosome dysfunction","volume":"115","author":"Narla","year":"2010","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1182\/blood.2019000947","article-title":"Diamond-Blackfan anemia","volume":"136","author":"Leblanc","year":"2020","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1182\/blood-2016-09-741835","article-title":"Widespread and dynamic translational control of red blood cell development","volume":"129","author":"Zhang","year":"2017","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1182\/blood-2017-08-799908","article-title":"HRI coordinates translation by eIF2\u03b1P and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency","volume":"131","author":"Zhang","year":"2018","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1182\/blood-2011-10-388132","article-title":"Heme-regulated eIF2\u03b1 kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis","volume":"119","author":"Suragani","year":"2012","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eadd3942","DOI":"10.1126\/sciadv.add3942","article-title":"Regulation of eIF4E guides a unique translational program to control erythroid maturation","volume":"8","author":"Forester","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/wrna.1354","article-title":"Structural insights into ribosome translocation","volume":"7","author":"Ling","year":"2016","journal-title":"WIREs RNA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/334170a0","article-title":"Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation","volume":"334","author":"Ryazanov","year":"1988","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1042\/BST20140323","article-title":"Regulation and roles of elongation factor 2 kinase","volume":"43","author":"Proud","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/aps.2015.123","article-title":"Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases","volume":"37","author":"Liu","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1172\/JCI122954","article-title":"Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer\u2019s disease model mice","volume":"129","author":"Beckelman","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s00109-020-01917-8","article-title":"Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target","volume":"98","author":"Karakas","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.biocel.2016.03.013","article-title":"Erythroid activator NF-E2, TAL1 and KLF1 play roles in forming the LCR HSs in the human adult \u03b2-globin locus","volume":"75","author":"Kim","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/s41596-018-0100-z","article-title":"Cell-type-specific quantification of protein synthesis in vivo","volume":"14","author":"Signer","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nature25741","article-title":"Population snapshots predict early haematopoietic and erythroid hierarchies","volume":"555","author":"Tusi","year":"2018","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1182\/blood-2003-05-1479","article-title":"Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: Functional analysis by a flow cytometry\u2013based novel culture system","volume":"102","author":"Zhang","year":"2003","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1182\/bloodadvances.2020003632","article-title":"Dynamic changes in murine erythropoiesis from birth to adulthood: Implications for the study of murine models of anemia","volume":"5","author":"Chen","year":"2020","journal-title":"Blood Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ajt.12526","article-title":"Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection","volume":"14","author":"Kim","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1039\/D0NP00011F","article-title":"Natural products targeting the elongation phase of eukaryotic protein biosynthesis","volume":"37","author":"Sasse","year":"2020","journal-title":"Nat. Prod. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/256665a0","article-title":"Mechanism of induction of haemolytic anaemia by phenylhydrazine","volume":"256","author":"Itano","year":"1975","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/voxs.12331","article-title":"Role of red blood cells in haemostasis and thrombosis","volume":"12","author":"Litvinov","year":"2017","journal-title":"ISBT Sci. Ser."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bosek, M., Ziomkowska, B., Pyskir, J., Wybranowski, T., Pyskir, M., Cyrankiewicz, M., Napi\u00f3rkowska, M., Durmowicz, M., and Kruszewski, S. (2022). Relationship between red blood cell aggregation and dextran molecular mass. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-24166-w"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/jth.14360","article-title":"Red blood cells: The forgotten player in hemostasis and thrombosis","volume":"17","author":"Weisel","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41408-021-00581-6","article-title":"JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis","volume":"11","author":"Guglielmelli","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1161\/ATVBAHA.119.312407","article-title":"Tuning the Thromboinflammatory Response to Venous Flow Interruption by the Ectonucleotidase CD39","volume":"39","author":"Anyanwu","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10059-012-0048-8","article-title":"Chromatin loop formation in the \u03b2-globin locus and its role in globin gene transcription","volume":"34","author":"Kim","year":"2012","journal-title":"Mol. Cells"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e208","DOI":"10.3324\/haematol.2014.106393","article-title":"NFE2 regulates transcription of multiple enzymes in the heme biosynthesis pathway","volume":"99","author":"Rheinemann","year":"2014","journal-title":"Haematologica"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1365-2141.2005.05416.x","article-title":"Gene expression profiling in polycythaemia vera: Overexpression of transcription factor NF-E2","volume":"129","author":"Goerttler","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1182\/blood-2009-11-254664","article-title":"AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2","volume":"116","author":"Wang","year":"2010","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.cell.2011.10.002","article-title":"Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes","volume":"147","author":"Ingolia","year":"2011","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1053\/j.seminhematol.2021.06.001","article-title":"Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization","volume":"58","author":"Maio","year":"2021","journal-title":"Semin. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/ncb3527","article-title":"Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation","volume":"19","author":"Liu","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.stemcr.2020.11.017","article-title":"Developmental Stage-Specific Changes in Protein Synthesis Differentially Sensitize Hematopoietic Stem Cells and Erythroid Progenitors to Impaired Ribosome Biogenesis","volume":"16","author":"Magee","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/ajh.27145","article-title":"Phenotypic and proteomic characterization of the human erythroid progenitor continuum reveal dynamic changes in cell cycle and in metabolic pathways","volume":"99","author":"Papoin","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_40","first-page":"2520","article-title":"Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A","volume":"141","author":"Phadke","year":"2023","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/iub.1024","article-title":"Integrating novel signaling pathways involved in erythropoiesis","volume":"64","author":"Ingley","year":"2012","journal-title":"IUBMB Life"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cell.2015.05.049","article-title":"Differential Requirements for eIF4E Dose in Normal Development and Cancer","volume":"162","author":"Truitt","year":"2015","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4801\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:34:17Z","timestamp":1760031257000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4801"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104801"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104801","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,16]]}}}