Architecture and function of the phagosome assembly site in autophagy

Autophagy is an intracellular degradation pathway by which cytosolic components and organelles are sequestered into a double-membrane vesicle and then delivered to the vacuole/lysosome for breakdown and recycling. It mediates cell homeostasis by the degradation of long-lived proteins and entire organelles. Autophagy also contributes to the adaptive response to starvation and various other stresses. Not surprisingly, defects in autophagy have been associated with several human diseases, including neurodegenerative disorders and cancer. During autophagy, membranes are initiated at the phagosome assembly site (PAS) close to the vacuole. The formation of these organelles called autophagosomes is regulated by the Atg1 kinase complex present at this location. Several components essential for autophagy induction have been identified and many of them are conserved from yeast to mammals, yet the mechanisms underlying this event remain elusive. As autophagosomes are not constitutively present in a cell but only formed upon certain stimuli, studying the formation of these organelles also helps us to understand organelle biogenesis in general. Knowledge of the PAS components and their interactions and dynamics is key to understanding how autophagy is regulated. I will dissect the architecture and function of the PAS and analyze the role of the Atg1 kinase complex in building this structure. I will use budding yeast as the main model system and apply a unique combination of biochemical and cell biological approaches in vitro and in vivo. These approaches will greatly advance our understanding of autophagy regulation and address a number of key questions on the regulation of organelle formation in general. Since many factors are evolutionary conserved in higher eukaryotes, this work will also help us to better understand diseases associated with autophagy misregulation.

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