Abstract
Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Here we use a pharmaceutical screen to discover new mechanisms for activation of autophagy. We identify a subset of pharmaceuticals inducing autophagic flux with effects in diverse cellular systems modelling specific stages of several human diseases such as HIV transmission and hyperphosphorylated tau accumulation in Alzheimer's disease. One drug, flubendazole, is a potent inducer of autophagy initiation and flux by affecting acetylated and dynamic microtubules in a reciprocal way. Disruption of dynamic microtubules by flubendazole results in mTOR deactivation and dissociation from lysosomes leading to TFEB (transcription factor EB) nuclear translocation and activation of autophagy. By inducing microtubule acetylation, flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin1 from Bcl-2-Beclin1 complexes for autophagy induction, thus uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment.
Highlights
Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases
We carried out screens for autophagy-modulating drugs in HeLa cells stably expressing mRFP-GFP-LC3B and processed ranked data for presumptive hits shown in Supplementary Table 1
Our data show that flubendazole, a compound that passed all stages of our screen for inducers of autophagy among pharmaceuticals, activates autophagy and autophagy flux by affecting multiple points of the autophagic pathway
Summary
Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin[1] from Bcl-2-Beclin[1] complexes for autophagy induction, uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment. Because of its significance in cancer[7], autophagy has been employed in clinical trials[3,11], through the use of rapamycin (autophagy activator through mTOR inhibition) and hydroxychloroquine, a generalized acidotropic neutralizer of the lysosomal organelles, and an inhibitor of autophagy These trials have yielded mixed outcomes with additional results pointing to possible personalized or otherwise tailored applications[11]. By dissecting flubendazole mechanism of action in autophagy induction, we uncovered a novel dual-role of microtubules, which, when affected simultaneously by this drug, resulted in induction of the complete autophagy pathway
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