title: mTOR-Controlled Autophagy Requires Intracellular Ca(2+) Signaling.
abstract: Autophagy is a lysosomal degradation pathway important for cellular homeostasis and survival. Inhibition of the mammalian target of rapamycin (mTOR) is the best known trigger for autophagy stimulation. In addition, intracellular Ca(2+) regulates autophagy, but its exact role remains ambiguous. Here, we report that the mTOR inhibitor rapamycin, while enhancing autophagy, also remodeled the intracellular Ca(2+)-signaling machinery. These alterations include a) an increase in the endoplasmic-reticulum (ER) Ca(2+)-store content, b) a decrease in the ER Ca(2+)-leak rate, and c) an increased Ca(2+) release through the inositol 1,4,5-trisphosphate receptors (IP3Rs), the main ER-resident Ca(2+)-release channels. Importantly, buffering cytosolic Ca(2+) with BAPTA impeded rapamycin-induced autophagy. These results reveal intracellular Ca(2+) signaling as a crucial component in the canonical mTOR-dependent autophagy pathway.
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Decuypere
authors.forename: Dimphny
authors.initials: D
authors.lastname: Kindt
authors.forename: Tomas
authors.initials: T
authors.lastname: Luyten
authors.forename: Kirsten
authors.initials: K
authors.lastname: Welkenhuyzen
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002118:Calcium; D020123:Sirolimus
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