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Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential

Chauhan, Santosh, Ahmed, Zahra, Bradfute, Steven B., Arko-Mensah, John, Mandell, Michael A., Won Choi, Seong, Kimura, Tomonori, Blanchet, Fabien, Waller, Anna, Mudd, Michal H., Jiang, Shanya, Sklar, Larry, Timmins, Graham S., Maphis, Nicole, Bhaskar, Kiran, Piguet, Vincent and Deretic, Vojo 2015. Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential. Nature Communications 6 , 8620. 10.1038/ncomms9620

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Additional Information: PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/2041-1723/ (accessed 26.2.16).
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 11 September 2015
Last Modified: 26 Dec 2017 20:42
URI: http://orca.cf.ac.uk/id/eprint/87218

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