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J Biol Chem. 2016 Apr 29;291(18):9700-11. doi: 10.1074/jbc.M115.704254. Epub 2016 Mar 5.

Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability.

Author information

1
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.
2
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.
3
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.
4
INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France.
5
ZIEL Research Center of Nutrition and Food Sciences, Molecular Nutrition and Biochemistry Unit, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising, Germany.
6
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.
7
Department of Medicine, University of California, San Diego, La Jolla, California 92093.
8
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.
9
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.

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.

KEYWORDS:

SLC3A2/CD98hc/4F2hc; SLC7 family; amino acid transport; cell proliferation; oxidative stress; peptide transport; stress response

PMID:
26945935
PMCID:
PMC4850307
DOI:
10.1074/jbc.M115.704254
[Indexed for MEDLINE]
Free PMC Article

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