Tyrosine kinase ABL inhibition activates TFEB and promotes cellular clearance in Niemann-Pick C disease

Lysosomes fulfill multiple functions involved in cellular homeostasis and their dysfunction leads to lysosomal storage disorders (LSD), characterized by substrate accumulation. The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis and autophagy. We previously demonstrated that the activation of the tyrosine kinase ABL leads to neuronal dysfunction and neurodegeneration in the Niemann-Pick type C (NPC) LSD, which is characterized by lysosomal cholesterol accumulation due to mutations in the genes encoding for the NPC1 and NPC2 proteins.

The aim of this thesis was to analyze if ABL regulates TFEB subcellular localization and if its inhibition ameliorates the cholesterol accumulation in NPC. Here, we show that ABL inhibition promotes cellular clearance in both pharmacological NPC models and human fibroblasts from NPC patients. Under pharmacological and genetic ABL inhibition, TFEB translocates into the nucleus ↓↓ independently of its well-known regulator: target of rapamycin complex 1 (mTORC1) ↓↓ and promotes the expression of its target genes. Active ABL1 phosphorylates TFEB on tyrosine and the inhibition of this kinase promotes autophagy flux, increases acidic organelles, lysosomal protein levels and a reduction in lysosomal cholesterol accumulation in in vitro and in vivo NPC models. Our data suggest that ABL regulates TFEB tyrosine phosphorylation and promotes TFEB localization in the cytoplasm.

In summary, we found a novel-signaling pathway, which involves the ABL kinase and TFEB. Therefore, inhibition of ABL/TFEB signaling pathway arises as a therapeutic target not only for NPC disease, but also for different diseases that are characterized by lysosomal dysfunction.

• Nombre: Pablo Contreras Soto
• Laboratorio: Señalización Celular
• Mención: Biología Celular y Molecular
• Director Tesis: Alejandra Álvarez