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Nat Commun. 2015 Oct 27;6:8620. doi: 10.1038/ncomms9620.

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

Author information

1
Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
2
Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK.
3
Department of Pathology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
4
College of Pharmacy, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
5
Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.

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.

PMID:
26503418
PMCID:
PMC4624223
DOI:
10.1038/ncomms9620
[Indexed for MEDLINE]
Free PMC Article

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