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

Santosh Chauhan, Zahra Ahmed, Steven B. Bradfute, John Arko-Mensah, Michael A. Mandell, Seong Won Choi, Tomonori Kimura, Fabien Blanchet, Anna Waller, Michal H. Mudd, Shanya Jiang, Larry Sklar, Graham S. Timmins, Nicole Maphis, Kiran Bhaskar, Vincent Piguet and Vojo Deretic ()
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Santosh Chauhan: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Zahra Ahmed: Cardiff Institute of Infection & Immunity, Cardiff University, School of Medicine, Henry Wellcome Building
Steven B. Bradfute: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
John Arko-Mensah: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Michael A. Mandell: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Seong Won Choi: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Tomonori Kimura: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Fabien Blanchet: Cardiff Institute of Infection & Immunity, Cardiff University, School of Medicine, Henry Wellcome Building
Anna Waller: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Michal H. Mudd: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Shanya Jiang: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Larry Sklar: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Graham S. Timmins: College of Pharmacy, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Nicole Maphis: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Kiran Bhaskar: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
Vincent Piguet: Cardiff Institute of Infection & Immunity, Cardiff University, School of Medicine, Henry Wellcome Building
Vojo Deretic: School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9620

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