Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux.
Autophagy
/ drug effects
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ antagonists & inhibitors
Cell Death
Cell Line, Tumor
Golgi Apparatus
/ drug effects
Humans
Hydrocarbons, Fluorinated
/ chemistry
Ion Transport
/ drug effects
Microtubule-Associated Proteins
/ genetics
Phosphorylation
Reactive Oxygen Species
/ metabolism
TOR Serine-Threonine Kinases
/ genetics
Up-Regulation
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 03 2019
11 03 2019
Historique:
received:
12
08
2018
accepted:
22
02
2019
revised:
08
01
2019
entrez:
13
3
2019
pubmed:
13
3
2019
medline:
21
5
2020
Statut:
epublish
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.
Identifiants
pubmed: 30858361
doi: 10.1038/s41419-019-1474-8
pii: 10.1038/s41419-019-1474-8
pmc: PMC6411943
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Hydrocarbons, Fluorinated
0
MAP1LC3A protein, human
0
Microtubule-Associated Proteins
0
Reactive Oxygen Species
0
TFEB protein, human
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
242Commentaires et corrections
Type : ErratumIn
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