Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.
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.
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.
Santosh
S
Chauhan
Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK.
Zahra
Z
Ahmed
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.
Steven B
SB
Bradfute
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.
John
J
Arko-Mensah
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.
Michael A
MA
Mandell
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.
Seong
S
Won Choi
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.
Tomonori
T
Kimura
Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK.
Fabien
F
Blanchet
Department of Pathology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
Anna
A
Waller
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.
Michal H
MH
Mudd
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.
Shanya
S
Jiang
Department of Pathology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
Larry
L
Sklar
College of Pharmacy, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
Graham S
GS
Timmins
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.
Nicole
N
Maphis
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.|Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
Kiran
K
Bhaskar
Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK.
Vincent
V
Piguet
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.|Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.
Vojo
V
Deretic
D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D001343:Autophagy / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008463:Mebendazole / Q000031:analogs & derivatives / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D054852:Small Molecule Libraries; C064972:TFEB protein, human; D008463:Mebendazole; C018945:flubendazole