Robin Ketteler: "Molecular Drug Targets in Autophagy"

Robin Ketteler
Translational Research Ressource Centre, MRC LMCB, University College London

Molecular Drug Targets in Autophagy

Autophagy is a cellular process that has multiple functions including the control of energy homeostasis, responding to cellular stresses and defense against pathogens. Autophagy plays important roles in the progression of various diseases including cancer, neurodegenerative diseases and Crohn’s disease as well as in infection and immunity. Despite recent advances in our understanding of the autophagy machinery, surprisingly little effort has been undertaken towards utilizing this knowledge in drug discovery processes. Several phenotypic screens have been undertaken to identify drug candidates that modulate this process. Current high-throughput screening approaches assay the formation of the autophagosome and very little is guided towards the identification of specific inhibitors of autophagy components.

The autophagy protease ATG4B is a key enzyme in this pathway that produces the mature form of ATG8 (LC3), an essential constituent of the autophagosomal membrane. In order to study the post-translational modulation of ATG4B, we have designed a novel reporter assay based on luciferase secretion that allowed us to investigate the regulation of ATG4B activity by high-throughput screening in vivo. I will present our recent high-throughput screening activities to identify regulators of ATG4B using RNAi as well as our translational screening approach that identifies novel inhibitors of autophagy.