The Birth of the Autophagosome (360G-Wellcome-313809_Z_24_Z)

Autophagy, the cell's recycling program, plays a critical role in maintaining cellular health through recycling nutrients and by removing threats to cellular survival, be it damaged organelles or invading pathogens. Significantly, impaired autophagy is now recognized as a hallmark of ageing, highlighting its importance alongside factors like loss of proteostasis or epigenetic alterations. The mechanism of autophagy initiation is understood in broad lines but the exact sequence of events, and how the autophagy machinery is integrated is not well understood. This is especially true for pathways of selective autophagy which target and eliminate specific cargo. My preliminary data has now uncovered a putative crucial new aspect of selective autophagy regulation through the GTPase Rab1 and its interaction with the autophagy machinery. Rab1 is critical for autophagy but has been largely overlooked. I propose that Rab1 is a cornerstone helping connect key autophagy machinery to autophagic cargo. I aim to first characterize the molecular mechanisms of Rab1-mediated signalling complexes. I will then characterize the mechanism and role of Rab1 in different forms of selective autophagy in cells, including mitophagy and aggrephagy. This proposal will advance the mechanistic insight of how autophagy is initiated and regulated with important implications for human health.