Investigating the mechanisms of TOLLIP function during autophagy (360G-Wellcome-202389_Z_16_Z)

Autophagy is an intracellular catabolic pathway that is required to maintain cell homeostasis during times of stress and starvation, as well as selectively degrade damaged organelles, protein aggregates, and intracellular pathogens. In order to develop future therapies that target this pathway to treat diseases such as cancer and neurodegeneration, further research is required to understand the mechanism of cargo selection, its mode of regulation, and its role in facilitating phenotypic alterations. Autophagy requires the integration of multiple signals, proteins, and lipids in order to identify the appropriate substrate, form the autophagosome, and fuse with the lysosome to degrade its cargo. This proposal will aim to elucidate the role of one such protein adaptor implicated in the autophagy pathway, Toll-interacting partner (TOLLIP), which has a crucial role in regulating both endocytic and autophagic cargo and their trafficking to the appropriate subcellular compartment. This project will utilise CRISPR-Cas9 gene knockout approaches and reconstitution experiments in an established human cell line to evaluate TOLLIP’s mechanistic role during autophagy.