1. Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.
- Author
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Chauhan S, Ahmed Z, Bradfute SB, Arko-Mensah J, Mandell MA, Won Choi S, Kimura T, Blanchet F, Waller A, Mudd MH, Jiang S, Sklar L, Timmins GS, Maphis N, Bhaskar K, Piguet V, and Deretic V
- Subjects
- Acetylation drug effects, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Humans, Lysosomes drug effects, Lysosomes metabolism, Mebendazole analogs & derivatives, Mebendazole pharmacology, Microtubules drug effects, Microtubules metabolism, Alzheimer Disease physiopathology, Autophagy drug effects, Drug Evaluation, Preclinical, Small Molecule Libraries pharmacology
- 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.
- Published
- 2015
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