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

Shaoyi Zhang; Yan Wang; Wei Xie; Ethan N.W. Howe; Nathalie Busschaert; Allan Sauvat; Marion Leduc; Lígia C. Gomes-da-Silva; Guo Chen; Isabelle Martins; Xiaxing Deng; Luigi Maiuri; Oliver Kepp; Thierry Soussi; Philip A. Gale; Naoufal Zamzami; Guido Kroemer

doi:10.1038/s41419-019-1474-8

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

Shaoyi Zhang, Yan Wang, Wei Xie, Ethan N.W. Howe, Nathalie Busschaert, Allan Sauvat, Marion Leduc, Lígia C. Gomes-da-Silva, Guo Chen, Isabelle Martins, Xiaxing Deng, Luigi Maiuri, Oliver Kepp, Thierry Soussi, Philip A. Gale, Naoufal Zamzami, Guido Kroemer

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

20 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Numéro d'article	242
journal	Cell Death and Disease
Volume	10
Numéro de publication	3
Les DOIs	https://doi.org/10.1038/s41419-019-1474-8
état	Publié - 1 mars 2019

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10.1038/s41419-019-1474-8

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Zhang, S., Wang, Y., Xie, W., Howe, E. N. W., Busschaert, N., Sauvat, A., Leduc, M., Gomes-da-Silva, L. C., Chen, G., Martins, I., Deng, X., Maiuri, L., Kepp, O., Soussi, T., Gale, P. A., Zamzami, N., & Kroemer, G. (2019). Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux. Cell Death and Disease, 10(3), Article 242. https://doi.org/10.1038/s41419-019-1474-8

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title = "Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux",

abstract = "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.",

author = "Shaoyi Zhang and Yan Wang and Wei Xie and Howe, {Ethan N.W.} and Nathalie Busschaert and Allan Sauvat and Marion Leduc and Gomes-da-Silva, {L{\'i}gia C.} and Guo Chen and Isabelle Martins and Xiaxing Deng and Luigi Maiuri and Oliver Kepp and Thierry Soussi and Gale, {Philip A.} and Naoufal Zamzami and Guido Kroemer",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41419-019-1474-8",

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Zhang, S, Wang, Y, Xie, W, Howe, ENW, Busschaert, N, Sauvat, A, Leduc, M, Gomes-da-Silva, LC, Chen, G, Martins, I, Deng, X, Maiuri, L, Kepp, O, Soussi, T, Gale, PA, Zamzami, N & Kroemer, G 2019, 'Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux', Cell Death and Disease, VOL. 10, Numéro 3, 242. https://doi.org/10.1038/s41419-019-1474-8

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T1 - Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux

AU - Zhang, Shaoyi

AU - Wang, Yan

AU - Xie, Wei

AU - Howe, Ethan N.W.

AU - Busschaert, Nathalie

AU - Sauvat, Allan

AU - Leduc, Marion

AU - Gomes-da-Silva, Lígia C.

AU - Chen, Guo

AU - Martins, Isabelle

AU - Deng, Xiaxing

AU - Maiuri, Luigi

AU - Kepp, Oliver

AU - Soussi, Thierry

AU - Gale, Philip A.

AU - Zamzami, Naoufal

AU - Kroemer, Guido

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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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