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.

• Authors: 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
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 3 Pg. 242 (03 11 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30858361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Hydrocarbons, Fluorinated
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Reactive Oxygen Species
• TFEB protein, human
• TOR Serine-Threonine Kinases

Topics

• Autophagy (drug effects, physiology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Cell Death
• Cell Line, Tumor
• Golgi Apparatus (drug effects)
• Humans
• Hydrocarbons, Fluorinated (chemistry, pharmacology)
• Ion Transport (drug effects)
• Microtubule-Associated Proteins (genetics, metabolism)
• Phosphorylation
• Reactive Oxygen Species (metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Up-Regulation