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Complete absence of GLUT1 does not impair human terminal erythroid differentiation.
Martins Freire, Catarina; King, Nadine R; Dzieciatkowska, Monika; Stephenson, Daniel; Moura, Pedro L; Dobbe, Johannes G G; Streekstra, Geert J; D'Alessandro, Angelo; Toye, Ashley M; Satchwell, Timothy J.
Afiliação
  • Martins Freire C; School of Biochemistry, University of Bristol, Bristol, United Kingdom.
  • King NR; School of Biochemistry, University of Bristol, Bristol, United Kingdom.
  • Dzieciatkowska M; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Stephenson D; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Moura PL; Department of Medicine, Center for Haematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Sweden.
  • Dobbe JGG; Biomedical Engineering and Physics, University of Amsterdam, Amsterdam UMC location, Amsterdam, The Netherlands.
  • Streekstra GJ; Biomedical Engineering and Physics, University of Amsterdam, Amsterdam UMC location, Amsterdam, The Netherlands.
  • D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Toye AM; School of Biochemistry, University of Bristol, Bristol, United Kingdom.
  • Satchwell TJ; School of Biochemistry, University of Bristol, Bristol, United Kingdom.
Blood Adv ; 8(19): 5166-5178, 2024 Oct 08.
Article em En | MEDLINE | ID: mdl-38916993
ABSTRACT
ABSTRACT The glucose transporter 1 (GLUT1) is 1 of the most abundant proteins within the erythrocyte membrane and is required for glucose and dehydroascorbic acid (vitamin C precursor) transport. It is widely recognized as a key protein for red cell structure, function, and metabolism. Previous reports highlighted the importance of GLUT1 activity within these uniquely glycolysis-dependent cells, in particular for increasing antioxidant capacity needed to avoid irreversible damage from oxidative stress in humans. However, studies of glucose transporter roles in erythroid cells are complicated by species-specific differences between humans and mice. Here, using CRISPR-mediated gene editing of immortalized erythroblasts and adult CD34+ hematopoietic progenitor cells, we generate committed human erythroid cells completely deficient in expression of GLUT1. We show that absence of GLUT1 does not impede human erythroblast proliferation, differentiation, or enucleation. This work demonstrates, to our knowledge, for the first time, generation of enucleated human reticulocytes lacking GLUT1. The GLUT1-deficient reticulocytes possess no tangible alterations to membrane composition or deformability in reticulocytes. Metabolomic analyses of GLUT1-deficient reticulocytes reveal hallmarks of reduced glucose import, downregulated metabolic processes and upregulated AMP-activated protein kinase signaling, alongside alterations in antioxidant metabolism, resulting in increased osmotic fragility and metabolic shifts indicative of higher oxidant stress. Despite detectable metabolic changes in GLUT1-deficient reticulocytes, the absence of developmental phenotype, detectable proteomic compensation, or impaired deformability comprehensively alters our understanding of the role of GLUT1 in red blood cell structure, function, and metabolism. It also provides cell biological evidence supporting clinical consensus that reduced GLUT1 expression does not cause anemia in GLUT1-deficiency syndrome.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Transportador de Glucose Tipo 1 Limite: Humans Idioma: En Revista: Blood Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Transportador de Glucose Tipo 1 Limite: Humans Idioma: En Revista: Blood Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido