Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11.
SLC7A11 encodes a subunit of the xCT cystine/glutamate amino-acid transport system and has a critical role in the generation of glutathione and the protection of cells from oxidative stress. Expression of SLC7A11 promotes tumorigenesis and chemotherapy resistance, but while SLC7A11 has been previously noted to be upregulated in hypoxic cells, its regulation has not been fully delineated. We have recently shown that nonsense-mediated RNA decay (NMD) is inhibited by cellular stresses generated by the tumor microenvironment, including hypoxia, and augments tumorigenesis. Here we demonstrate that the inhibition of NMD by various cellular stresses leads to the stabilization and upregulation of SLC7A11 mRNA and protein. The inhibition of NMD and upregulation of SLC7A11 augments intracellular cystine transport and increases intracellular levels of cysteine and glutathione. Accordingly, the inhibition of NMD protects cells against oxidative stress via SLC7A11 upregulation. Together our studies identify a mechanism for the dynamic regulation of SLC7A11, through the stress-inhibited regulation of NMD, and add to the growing evidence that the inhibition of NMD is an adaptive response.
Department of Medicine, New York University School of Medicine, New York, NY, USA.
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1] Department of Medicine, New York University School of Medicine, New York, NY, USA [2] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA [3] NYU Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
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D027182:Amino Acid Transport System y+ / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003553:Cystine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D000860:Hypoxia; D015151:Immunoblotting; D042541:Intracellular Space / Q000378:metabolism; D018384:Oxidative Stress; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation
D027182:Amino Acid Transport System y+; D012333:RNA, Messenger; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D003553:Cystine; D005978:Glutathione