Mechanisms and hierarchy in autophagosome formation

In my lab we want to understand how the cellular waste disposal system, called autophagy, works. Defects in autophagy have been associated with several human diseases, including neurodegenerative disorders and cancer. During autophagy, membranes are initiated at the pre-autophagosomal structure close to the vacuole. The formation of these organelles called autophagosomes is regulated by the Atg1 kinase complex present at and part of this structure, which itself is under the control of the target of rapamycin kinase. Several components essential for autophagy induction have been identified in yeast and 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. Mechanistic insight into the regulation of autophagosome formation is key to understand how autophagy is regulated. Our goal is to understand the signaling events inducing and regulating autophagic cargo uptake into autophagosomes and their subsequent delivery to the vacuole. We use a combination of biochemical, genetic and cell biological approaches including novel fluorescent microscopy methods. We will create an artificial autophagy cargo, which will allow us to study the players needed for packaging as well as the order of events from the early beginning of the process, which wasn`t possible to study to date. Using such a novel system provides a niche for our research. 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.

A clean apartment and workplace, while certainly important, are not strictly necessary in order to survive. For cells, however, tidying up is absolutely vital. The responsible process is called autophagy, which has now become widely known due to Yoshinori Ohsumi's winning of the Nobel Prize in Medicine in October 2016. During autophagy, a defined set of proteins coordinates the removal of viruses, bacteria, and damaged or superfluous material from a cell. Autophagy also enables cells to survive times of starvation, by degrading the cell's own components to recycle their building blocks - similar to recycling stations in a town. This process needs to be tightly controlled to prevent the removal of structures that are still required in the cell. In this project we aimed at understanding the molecular mechanisms of early autophagy induction, i.e. the assembly of the autophagic machinery at the lytic compartment. We found that the machinery proteins only assemble once the cargo has attached to the lytic compartment, and does not assemble on the cargo in the cytosol. Further work addressed the requirement of individual factors during this assembly as well as the anchoring of autophagic membranes at the lytic compartment. Together, our work provides new insight into the assembly and hierarchy of autophagy proteins at the lytic compartment early in the autophagic pathway. The detailed study of such fundamental cellular processes is crucial for the understanding of diseases that go hand in hand with these events - in the case of autophagy, Alzheimer's disease or cancer. In the long run, this will help to better treat or perhaps even prevent these illnesses.