INVESTIGATING NOVEL ROLES OF GELSOLIN IN EARLY AUTOPHAGY

Abstract

Autophagy is an important process to maintain cell survival under stressful conditions, but it can also promote cancer progression by conferring chemotherapeutic drug resistance to tumour cells. Gelsolin, a cytoskeletal actin-binding protein, is able to augment the levels of autophagy in colorectal cancer cells, making them less susceptible to 5-fluorouracil (5-FU). However, the mechanism of action of gelsolin in autophagy regulation has not been fully elucidated. In this study, gelsolin was shown to modulate the stages of early autophagy by recruitment of the ULK1 initiation complex on autophagosome formation sites as well as the trafficking of Atg9a during the initiation and phagophore elongation steps. The effects of gelsolin on the early stages of autophagy were determined to be dependent on its ability to bind to actin filaments as mutations inhibiting the optimal binding of gelsolin to F-actin also decreased the recruitment and trafficking of the ULK1 complex and Atg9a, respectively.