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Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux

Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores...

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Autores principales: Zhang, Shaoyi, Wang, Yan, Xie, Wei, Howe, Ethan N. W., Busschaert, Nathalie, Sauvat, Allan, Leduc, Marion, Gomes-da-Silva, Lígia C., Chen, Guo, Martins, Isabelle, Deng, Xiaxing, Maiuri, Luigi, Kepp, Oliver, Soussi, Thierry, Gale, Philip A., Zamzami, Naoufal, Kroemer, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411943/
https://www.ncbi.nlm.nih.gov/pubmed/30858361
http://dx.doi.org/10.1038/s41419-019-1474-8
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author Zhang, Shaoyi
Wang, Yan
Xie, Wei
Howe, Ethan N. W.
Busschaert, Nathalie
Sauvat, Allan
Leduc, Marion
Gomes-da-Silva, Lígia C.
Chen, Guo
Martins, Isabelle
Deng, Xiaxing
Maiuri, Luigi
Kepp, Oliver
Soussi, Thierry
Gale, Philip A.
Zamzami, Naoufal
Kroemer, Guido
author_facet Zhang, Shaoyi
Wang, Yan
Xie, Wei
Howe, Ethan N. W.
Busschaert, Nathalie
Sauvat, Allan
Leduc, Marion
Gomes-da-Silva, Lígia C.
Chen, Guo
Martins, Isabelle
Deng, Xiaxing
Maiuri, Luigi
Kepp, Oliver
Soussi, Thierry
Gale, Philip A.
Zamzami, Naoufal
Kroemer, Guido
author_sort Zhang, Shaoyi
collection PubMed
description Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores block autophagic flux in spite of the fact that they activate the pro-autophagic transcription factor EB (TFEB) coupled to the inhibition of the autophagy-suppressive mTORC1 kinase activity. Two synthetic chloride transporters (SQ1 and SQ2) caused a partially TFEB-dependent relocation of the autophagic marker LC3 to the Golgi apparatus. Inhibition of TFEB activation using a calcium chelator or calcineurin inhibitors reduced the formation of LC3 puncta in cells, yet did not affect the cytotoxic action of SQ1 and SQ2 that could be observed after prolonged incubation. In conclusion, the squaramide-based synthetic chloride transporters studied in this work (which can also dissipate pH gradients) are probably not appropriate for the treatment of cystic fibrosis yet might be used for other indications such as cancer.
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spelling pubmed-64119432019-03-12 Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux Zhang, Shaoyi Wang, Yan Xie, Wei Howe, Ethan N. W. Busschaert, Nathalie Sauvat, Allan Leduc, Marion Gomes-da-Silva, Lígia C. Chen, Guo Martins, Isabelle Deng, Xiaxing Maiuri, Luigi Kepp, Oliver Soussi, Thierry Gale, Philip A. Zamzami, Naoufal Kroemer, Guido Cell Death Dis Article Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores block autophagic flux in spite of the fact that they activate the pro-autophagic transcription factor EB (TFEB) coupled to the inhibition of the autophagy-suppressive mTORC1 kinase activity. Two synthetic chloride transporters (SQ1 and SQ2) caused a partially TFEB-dependent relocation of the autophagic marker LC3 to the Golgi apparatus. Inhibition of TFEB activation using a calcium chelator or calcineurin inhibitors reduced the formation of LC3 puncta in cells, yet did not affect the cytotoxic action of SQ1 and SQ2 that could be observed after prolonged incubation. In conclusion, the squaramide-based synthetic chloride transporters studied in this work (which can also dissipate pH gradients) are probably not appropriate for the treatment of cystic fibrosis yet might be used for other indications such as cancer. Nature Publishing Group UK 2019-03-11 /pmc/articles/PMC6411943/ /pubmed/30858361 http://dx.doi.org/10.1038/s41419-019-1474-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zhang, Shaoyi
Wang, Yan
Xie, Wei
Howe, Ethan N. W.
Busschaert, Nathalie
Sauvat, Allan
Leduc, Marion
Gomes-da-Silva, Lígia C.
Chen, Guo
Martins, Isabelle
Deng, Xiaxing
Maiuri, Luigi
Kepp, Oliver
Soussi, Thierry
Gale, Philip A.
Zamzami, Naoufal
Kroemer, Guido
Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title_full Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title_fullStr Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title_full_unstemmed Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title_short Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
title_sort squaramide-based synthetic chloride transporters activate tfeb but block autophagic flux
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411943/
https://www.ncbi.nlm.nih.gov/pubmed/30858361
http://dx.doi.org/10.1038/s41419-019-1474-8
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