Phenotypic Screening Paradigms for Autophagy Pathway Regulators Beat Nyfeler Novartis Institutes for BioMedical Research, Switzerland
Autophagy is a catabolic pathway which supports cellular homeostasis by delivering damaged organelles, pathogens or protein aggregates into lysosomes for degradation. Hence, modulation of autophagy may be exploited to modify various diseases. To identify novel pathway nodes, we established phenotypic pooled CRISPR screening paradigms and mapped regulators of autophagy cargo and cargo receptors in mammalian cells. As proof of concept, we performed a genome-wide screen for the autophagy cargo receptor p62 and validated mTOR signalling and the entire macroautophagy machinery as key regulators of p62 turnover. More recently, we used this approach to identify an alternative lysosomal transport pathway for ferritin which requires FIP200, ATG9A, VPS34 and TAX1BP1, but lacks involvement of the ATG8 lipidation machinery. Here, we will present our progress in applying phenotypic screening paradigms to identify novel autophagy pathway nodes.
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