title: Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability.
abstract: CD98hc functions as an amino acid (AA) transporter (together with another subunit) and integrin signaling enhancer. It is overexpressed in highly proliferative cells in both physiological and pathological conditions. CD98hc deletion induces strong impairment of cell proliferation in vivo and in vitro Here, we investigate CD98hc-associated AA transport in cell survival and proliferation. By using chimeric versions of CD98hc, the two functions of the protein can be uncoupled. Although recovering the CD98hc AA transport capacity restores the in vivo and in vitro proliferation of CD98hc-null cells, reconstitution of the integrin signaling function of CD98hc is unable to restore in vitro proliferation of those cells. CD98hc-associated transporters (i.e. xCT, LAT1, and y(+)LAT2 in wild-type cells) are crucial to control reactive oxygen species and intracellular AA levels, thus sustaining cell survival and proliferation. Moreover, in CD98hc-null cells the deficiency of CD98hc/xCT cannot be compensated, leading to cell death by ferroptosis. Supplementation of culture media with β-mercaptoethanol rescues CD98hc-deficient cell survival. Under such conditions null cells show oxidative stress and intracellular AA imbalance and, consequently, limited proliferation. CD98hc-null cells also present reduced intracellular levels of branched-chain and aromatic amino acids (BCAAs and ARO AAs, respectively) and induced expression of peptide transporter 1 (PEPT1). Interestingly, external supply of dipeptides containing BCAAs and ARO AAs rescues cell proliferation and compensates for impaired uptake of CD98hc/LAT1 and CD98hc/y(+)LAT2. Our data establish CD98hc as a master protective gene at the cross-road of redox control and AA availability, making it a relevant therapeutic target in cancer.
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France, larual_rb@yahoo.es.
authors.forename: Laura R
authors.identifier: http://orcid.org/0000-0001-5363-7433
authors.initials: LR
authors.lastname: de la Ballina
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, Spanish Biomedical Research Network in Rare Diseases (CIBERER U-731), 08028 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Cano-Crespo
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, The Andalusian Cellular Reprogramming Laboratory (LARCEL), Fundación Progreso y Salud, 41092 Seville, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: González-Muñoz
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, Spanish Biomedical Research Network in Rare Diseases (CIBERER U-731), 08028 Barcelona, Spain.
authors.forename: Susanna
authors.initials: S
authors.lastname: Bial
authors.affiliation: INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France.
authors.forename: Soline
authors.initials: S
authors.lastname: Estrach
authors.affiliation: INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cailleteau
authors.affiliation: INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Tissot
authors.affiliation: ZIEL Research Center of Nutrition and Food Sciences, Molecular Nutrition and Biochemistry Unit, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM), 08028 Barcelona, Spain, and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.affiliation: From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, Spanish Biomedical Research Network in Rare Diseases (CIBERER U-731), 08028 Barcelona, Spain, manuel.palacin@irbbarcelona.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.affiliation: INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France, chloe.feral@inserm.fr.
authors.forename: Chloé C
authors.initials: CC
authors.lastname: Féral
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D027241:Amino Acid Transport System y+L; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000378:metabolism*; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D000596:Amino Acids; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027301:Fusion Regulatory Protein 1, Light Chains; D017382:Reactive Oxygen Species; C518286:SLC7A8 protein, mouse; C518287:Slc7a7 protein, mouse
keywords: SLC3A2/CD98hc/4F2hc; SLC7 family; amino acid transport; cell proliferation; oxidative stress; peptide transport; stress response