c-Abl Inhibition Activates TFEB: A Novel Way To Promote Cellular Clearance in Lysosomal Disorders

Lysosomes fulfill multiple functions involved in cellular homeostasis and their dysfunction leads to substrates accumulation causing neurodegenerative diseases. The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mTORC1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy and exocytosis. c-Abl inhibition in pharmacological Niemann Pick type-C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB dependent manner. In genetic NPC models, c-Abl inhibition promotes cellular clearance through TFEB activation. We propose the modulation of this novel c-Abl/TFEB axis, using the FDA-approved drugs Imatinib or Nilotinib, as a therapeutic strategy to treat different neurodegenerative storage disorders.