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      Erythroid SLC7A5/SLC3A2 amino acid carrier controls red blood cell size and maturation

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          Summary

          Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.

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          Highlights

          • •

            Expression of SLC7A5/SLC3A2 amino acid carrier in immature erythroid cells

          • •

            Erythropoietin regulates SLC7A5/SLC3A2 expression

          • •

            Loss of SLC7A5 reduces size, hemoglobin and mTORC1 activity of erythroid cells

          • •

            SLC7A5 sustains CD71 expression and mitochondrial activity in circulating reticulocytes

          Abstract

          Molecular physiology; Cell biology.

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          Most cited references77

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          Bidirectional transport of amino acids regulates mTOR and autophagy.

          Paul Nicklin, Philip Bergman, Bailin Zhang … (2009)
          Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.
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            Regulation of translation initiation in eukaryotes: mechanisms and biological targets.

            Nahum Sonenberg, Alan Hinnebusch (2009)
            Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific translational control, particularly in mammalian systems.
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              Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins.

              H. Sato, M. TAMBA, T Ishii … (1999)
              Transport system xc- found in plasma membrane of cultured mammalian cells is an exchange agency for anionic amino acids with high specificity for anionic form of cystine and glutamate. We have isolated cDNA encoding the transporter for system xc- from mouse activated macrophages by expression in Xenopus oocytes. The expression of system xc- activity in oocytes required two cDNA transcripts, and the sequence analysis revealed that one is identical with the heavy chain of 4F2 cell surface antigen (4F2hc) and the other is a novel protein of 502 amino acids with 12 putative transmembrane domains. The latter protein, named xCT, showed a significant homology with those recently reported to mediate cationic or zwitterionic amino acid transport when co-expressed with 4F2hc. Thus xCT is a new member of a family of amino acid transporters that form heteromultimeric complex with 4F2hc, with a striking difference in substrate specificity. The expression of system xc- was highly regulated, and Northern blot analysis demonstrated that the expression of both 4F2hc and xCT was enhanced in macrophages stimulated by lipopolysaccharide or an electrophilic agent. However, the expression of xCT was more directly correlated with the system xc- activity.
              Article 0 comments Cited 306 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Julián Aragonés
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 05 December 2022
                Publication date Collection: 20 January 2023
                Publication date (Electronic): 05 December 2022
                Volume: 26
                Issue: 1
                Electronic Location Identifier: 105739
                Affiliations
                [1 ]Research Unit, Hospital of Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid, 28009 Madrid, Spain
                [2 ]Immunology Department, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain
                [3 ]Departamento de Química Física, Universidad Complutense de Madrid, Ciudad Universitaria s/n, Madrid, Spain
                [4 ]Translational Biophysics. Instituto de Investigación Sanitaria Hospital Doce de Octubre (Imas12), Madrid, Spain
                [5 ]Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Ctra. Pozuelo-Majadahonda Km 1,800, 28223, Pozuelo de Alarcón, Madrid, Spain
                [6 ]Nephrology Department, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain
                [7 ]Hematology Department, Hospital Universitario La Paz, Madrid, Spain
                [8 ]Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
                [9 ]Pathology Anatomy Department, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
                [10 ]CIBER de Enfermedades Cardiovasculares, Carlos III Health Institute, Madrid, Spain
                Author notes
                [∗ ]Corresponding author julian.aragones@ 123456uam.es
                [11]

                These authors contributed equally

                [12]

                These authors contributed equally

                [13]

                Lead contact

                Article
                Publisher Item ID: S2589-0042(22)02012-0 Publisher ID: 105739
                DOI: 10.1016/j.isci.2022.105739
                PMC ID: 9792907
                SO-VID: 4476be16-060e-4f97-a3c0-3b0d923895dc
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 29 March 2022
                Date revision received : 31 October 2022
                Date accepted : 1 December 2022
                Categories
                Subject: Article

                Keywords: molecular physiology,cell biology
                Data availability:
                Keywords: molecular physiology, cell biology

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