TY - JOUR
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
N1 - Publisher Copyright:
© 2019, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85062765903&partnerID=8YFLogxK
U2 - 10.1038/s41419-019-1474-8
DO - 10.1038/s41419-019-1474-8
M3 - Article
C2 - 30858361
AN - SCOPUS:85062765903
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - 242
ER -