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

dc.contributor.authorde la Ballina, Laura R
dc.contributor.authorCano-Crespo, Sara
dc.contributor.authorGonzález-Muñoz, Elena
dc.contributor.authorBial, Susanna
dc.contributor.authorEstrach, Soline
dc.contributor.authorCailleteau, Laurence
dc.contributor.authorTissot, Floriane
dc.contributor.authorDaniel, Hannelore
dc.contributor.authorZorzano, Antonio
dc.contributor.authorGinsberg, Mark H
dc.contributor.authorPalacín, Manuel
dc.contributor.authorFéral, Chloé C
dc.date.accessioned2023-01-25T08:31:16Z
dc.date.available2023-01-25T08:31:16Z
dc.date.issued2016-03-05
dc.description.abstractCD98hc 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.
dc.identifier.doi10.1074/jbc.M115.704254
dc.identifier.essn1083-351X
dc.identifier.pmcPMC4850307
dc.identifier.pmid26945935
dc.identifier.pubmedURLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850307/pdf
dc.identifier.unpaywallURLhttp://www.jbc.org/content/291/18/9700.full.pdf
dc.identifier.urihttp://hdl.handle.net/10668/9898
dc.issue.number18
dc.journal.titleThe Journal of biological chemistry
dc.journal.titleabbreviationJ Biol Chem
dc.language.isoen
dc.organizationFundación Pública Andaluz Progreso y Salud-FPS
dc.page.number9700-11
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, Non-U.S. Gov't
dc.rightsAttribution 4.0 International
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectSLC3A2/CD98hc/4F2hc
dc.subjectSLC7 family
dc.subjectamino acid transport
dc.subjectcell proliferation
dc.subjectoxidative stress
dc.subjectpeptide transport
dc.subjectstress response
dc.subject.meshAmino Acid Transport System y+
dc.subject.meshAmino Acid Transport System y+L
dc.subject.meshAmino Acids
dc.subject.meshAnimals
dc.subject.meshBiological Transport, Active
dc.subject.meshCell Differentiation
dc.subject.meshCell Line
dc.subject.meshCell Proliferation
dc.subject.meshCell Survival
dc.subject.meshFusion Regulatory Protein 1, Heavy Chain
dc.subject.meshFusion Regulatory Protein 1, Light Chains
dc.subject.meshGene Deletion
dc.subject.meshMice
dc.subject.meshMouse Embryonic Stem Cells
dc.subject.meshOxidative Stress
dc.subject.meshReactive Oxygen Species
dc.titleAmino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability.
dc.typeresearch article
dc.type.hasVersionVoR
dc.volume.number291
dspace.entity.typePublication

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