Molecular mechanisms of spatial protein quality control

How do cells organize the cytoplasm in response to acute heat stress and adapt to protein misfolding stress? We found that heat stress causes a rapid reorganization of protein quality components and misfolded proteins into inclusion bodies in budding yeast (Malinovska et al., 2012; Alberti, 2012). Protein misfolding and aggregation were not sufficient to induce the formation of these inclusion bodies. Rather, their assembly required the concerted action of molecular chaperones, protein-sorting factors and protein-sequestration factors, thus defining a minimal machinery for spatial protein quality control. This allowed us to propose a model wherein the amount of soluble misfolded proteins is controlled through regulated compartment formation in the cytoplasm, thus allowing cells to rapidly adapt to acute stress.

We also became interested in the related question of how damage such as protein aggregates is partitioned during cell division. Additional findings show that in budding yeast, protein damage is retained in the aging mother cell lineage, whereas daughter cells are damage-free. Because budding yeast divides asymmetrically, we also investigated this question in the symmetrically dividing fission yeast. In collaboration with Iva Tolic at the MPI-CBG, we found that fission yeast does not age under normal conditions and that damage is partitioned equally between daughter cells (Coelho et al., 2013; 2014).

Future Plans:

Our future plan is to gain further insight into the functional role of the spatial protein quality control machinery. Our preliminary results suggest that this machinery affects protein degradation, metabolism and aging. Genetic and cell biological studies are underway to firmly establish a role in these areas. The expected outcome is a novel conceptual understanding of protein aggregation as a highly dynamic, controlled and spatially confined cellular process. Our findings will significantly improve our understanding of how damaged proteins are managed in stressed cells and they will reveal important links between the spatial protein quality control machinery and age-related diseases.