R03: Targeted Protein Degradation in Nuclear Quality Control Condensates

Targeted protein degradation can be enhanced by compartmentalizing protein degradation through the formation of proteolytic centres in the cell. These proteolytic centres represent subcellular membrane-less compartments where defective proteins and unassembled subunits of protein complexes may accumulate before their degradation. Moreover, proteolytic centres may be particularly relevant during conditions that challenge protein and organelle homeostasis, which can result in the overload of the ubiquitin–proteasome system and autophagy. The formation of these proteolytic condensates appears to be driven by multivalent, weak interactions between proteasome shuttle proteins and poly-ubiquitin chains. It remains largely unknown which stress conditions trigger the formation of these proteolytic centres and how they are resolved. Which proteins are targeted to and are subsequently degraded in these condensates, and what is the role of proteasome shuttle proteins and E3 ligases in target selection and condensate regulation? What are the biophysical and chemical principles that govern the underlying processes? To tackle these questions, we will combine expertise from the participating groups in mass-spectrometry-based proteomics, molecular biology, biochemistry, bioinformatics, and coarse-grained molecular modelling. With this highly interdisciplinary approach, we will be able to understand compartmentalized protein degradation from its very atomistic biopolymer aspects to its broad functional implications for cell survival and adaptation.