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Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis

Although essential amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) and the integrated stress response (ISR), the role of cysteine is unknown. We found that in hepatoma HepG2 cells, cystine (oxidized form of cysteine) activated mTORC1 and suppressed the ISR. Cystine deprivatio...

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Autores principales: Yu, Xinlei, Long, Yun Chau
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948025/
https://www.ncbi.nlm.nih.gov/pubmed/27425006
http://dx.doi.org/10.1038/srep30033
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author Yu, Xinlei
Long, Yun Chau
author_facet Yu, Xinlei
Long, Yun Chau
author_sort Yu, Xinlei
collection PubMed
description Although essential amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) and the integrated stress response (ISR), the role of cysteine is unknown. We found that in hepatoma HepG2 cells, cystine (oxidized form of cysteine) activated mTORC1 and suppressed the ISR. Cystine deprivation induced GSH efflux and extracellular degradation, which aimed to restore cellular cysteine. Inhibition of γ-glutamyl transpeptidase (GGT) impaired the ability of GSH or cell-permeable GSH to restore mTORC1 signaling and the ISR, suggesting that the capacity of GSH to release cysteine, but not GSH per se, regulated the signaling networks. Inhibition of protein translation restored both mTORC1 signaling and the ISR during cystine starvation, suggesting the bulk of cellular cysteine was committed to the biosynthetic process. Cellular cysteine and GSH displayed overlapping protective roles in the suppression of ferroptosis, further supporting their cooperation in the regulation of cell signaling. Thus, cellular cysteine and its derivative GSH cooperate to regulate mTORC1 pathway, the ISR and ferroptosis.
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spelling pubmed-49480252016-07-26 Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis Yu, Xinlei Long, Yun Chau Sci Rep Article Although essential amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) and the integrated stress response (ISR), the role of cysteine is unknown. We found that in hepatoma HepG2 cells, cystine (oxidized form of cysteine) activated mTORC1 and suppressed the ISR. Cystine deprivation induced GSH efflux and extracellular degradation, which aimed to restore cellular cysteine. Inhibition of γ-glutamyl transpeptidase (GGT) impaired the ability of GSH or cell-permeable GSH to restore mTORC1 signaling and the ISR, suggesting that the capacity of GSH to release cysteine, but not GSH per se, regulated the signaling networks. Inhibition of protein translation restored both mTORC1 signaling and the ISR during cystine starvation, suggesting the bulk of cellular cysteine was committed to the biosynthetic process. Cellular cysteine and GSH displayed overlapping protective roles in the suppression of ferroptosis, further supporting their cooperation in the regulation of cell signaling. Thus, cellular cysteine and its derivative GSH cooperate to regulate mTORC1 pathway, the ISR and ferroptosis. Nature Publishing Group 2016-07-18 /pmc/articles/PMC4948025/ /pubmed/27425006 http://dx.doi.org/10.1038/srep30033 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Yu, Xinlei
Long, Yun Chau
Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title_full Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title_fullStr Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title_full_unstemmed Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title_short Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
title_sort crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948025/
https://www.ncbi.nlm.nih.gov/pubmed/27425006
http://dx.doi.org/10.1038/srep30033
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