Targeted protein degradation - from small molecules to complex organelles

The targeted degradation of proteins is of utmost importance for the well-being of our cells and thus for the entire organism. When proteins unfold, they can form aggregates and ultimately result in cell death. These proteins must therefore be degraded swiftly. In addition, proteins must be removed in a targeted manner in order to allow the activation, but also the deactivation of signal transduction pathways. Furthermore, protein degradation plays an essential role during the differentiation of cells. Defects in the targeted degradation of proteins can result in diseases such as cancer and neurodegeneration. Due to the great importance of targeted protein degradation, sophisticated systems have evolved to mediate this process. Among the most important systems are the ubiquitin-proteasome system (UPS) as well as autophagy. In the UPS, the proteins destined for degradation are marked by a small protein called ubiquitin. This ubiquitin mark is recognized by the proteasome, the protein is unfolded and finally degraded within the proteasome. In autophagy, target proteins are recognized by dedicated receptors, also often via ubiquitin marks, enveloped by a double membrane and eventually degraded within lysosomes. How exactly proteins are marked, and in particular which signals decide whether a protein is degraded by the UPS or via autophagy is unclear. Within this collaborative research consortium, we will investigate how target proteins are channeled towards the UPS or to autophagy. We will also explore how proteins are degraded in the nucleus, where autophagy cannot be functional. Furthermore, we will study how the degradation systems can be reprogrammed using small molecules, in the long run potentially allowing the therapeutic intervention into diseases. To reach these ambitious goals, we have assembled a team of outstanding scientists which can resort to a plethora of model organisms and methods. The synergies within the consortium will unravel internationally visible and biomedically relevant mechanisms of this important process.