A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations
authors Busschaert, N; Park, SH; Baek, KH; Choi, YP; Park, J; Howe, ENW; Hiscock, JR; Karagiannidis, LE; Marques, I; Felix, V; Namkung, W; Sessler, JL; Gale, PA; Shin, I
nationality International
journal NATURE CHEMISTRY
keywords TRANSMEMBRANE ANION TRANSPORTERS; SMALL-MOLECULE; CYTOCHROME-C; DEATH; ATPASE; ACIDIFICATION; TRAFFICKING; DISSECTION; LYSOSOMES; MEMBRANES
abstract Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.
publisher NATURE PUBLISHING GROUP
issn 1755-4330
year published 2017
volume 9
issue 7
beginning page 667
ending page 675
digital object identifier (doi) 10.1038/NCHEM.2706
web of science category Chemistry, Multidisciplinary
subject category Chemistry
unique article identifier WOS:000404056800014
  ciceco authors
  impact metrics
times cited (wos core): 4
journal impact factor (jcr 2016): 25.870
5 year journal impact factor (jcr 2016): 28.129
category normalized journal impact factor percentile (jcr 2016): 97.892
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