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

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

2041-4889
1-11
Zhang, Shaoyi
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Wang, Yan
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Xie, Wei
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Howe, Ethan N.W.
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Busschaert, Nathalie
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Sauvat, Allan
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Leduc, Marion
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Gomes-da-Silva, Lígia C.
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Chen, Guo
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Martins, Isabelle
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Deng, Xiaxing
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Maiuri, Luigi
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Kepp, Oliver
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Soussi, Thierry
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Gale, Philip A.
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Zamzami, Naoufal
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Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26
Zhang, Shaoyi
f326269c-4018-4277-85c7-1e608b9a0f57
Wang, Yan
f4f6e873-392a-430a-b8e2-a80a0416ea57
Xie, Wei
f914674b-ec65-446f-b4dc-aab155152bd6
Howe, Ethan N.W.
be05ae9a-02e0-443b-97b2-d65cc387af40
Busschaert, Nathalie
9abe79c0-7540-4677-bf27-84e8e0e048f6
Sauvat, Allan
1518f63b-6934-4118-87e8-813a8bcbffe5
Leduc, Marion
19d823a8-c366-4da2-9d78-ba7708d9f4a1
Gomes-da-Silva, Lígia C.
c689550d-8014-4174-ad9a-ecbd4ccac515
Chen, Guo
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Martins, Isabelle
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Deng, Xiaxing
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Maiuri, Luigi
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Kepp, Oliver
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Soussi, Thierry
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Gale, Philip A.
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Zamzami, Naoufal
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Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26

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 and Kroemer, Guido (2019) Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux. Cell Death and Disease, 10 (3), 1-11, [242]. (doi:10.1038/s41419-019-1474-8).

Record type: Article

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.

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Accepted/In Press date: 22 February 2019
e-pub ahead of print date: 11 March 2019

Identifiers

Local EPrints ID: 429289
URI: http://eprints.soton.ac.uk/id/eprint/429289
ISSN: 2041-4889
PURE UUID: a5ca00ff-3c13-495e-a3ca-26060a972196
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910

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Date deposited: 26 Mar 2019 17:30
Last modified: 20 Apr 2021 01:38

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Contributors

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

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