Molecular Mechanisms of Autophagy

Autophagy is an evolutionarily conserved important cellular process, that plays an essential role during starvation, pathogen defense and in the removal of protein aggregates and damaged organelles. Misregulated or defective autophagy can result in neurodegeneration and premature aging. Yeast genetic screens have led to the identification of key players regulating and executing autophagy. The challenge now is to assign functions to these molecules leading to an understanding of the mechanisms that orchestrate autophagy.
Autophagy is triggered by an upstream signal such as starvation, the detection of pathogenic microorganisms in the cytosol or by damaged mitochondria. This signal triggers the most enigmatic and fascinating step of autophagy, the de novo formation of autophagosomes. Initially a small double membrane bound structure is formed, which grows and adopts the shape of a cup. This cup-shaped structure eventually fuses at its rims to form a double membrane bound organelle enclosing a part of the cell’s cytoplasm. The autophagosome then fuses with components of the classical endosomal system thereby maturing to an autolysosome within which the content is degraded.
We will employ biochemistry, light- and electron microscopy to investigate these mechanisms. Our ultimate goal is to reconstitute autophagy in vitro and to translate our findings back to in vivo models. Our findings will give important insights into the generation of membrane curvature, the formation of specialized membrane domains and organelle formation in general.

 
 

Massive autophagsome formation (green) in the vicinity of an intracellular pathogen (red). The nucleus is shown in blue. (Source: Martens et al., PLoS Path 2005)