Molecular mechanisms of spatial protein quality control

Abstract

Evidence is now accumulating that damaged proteins are not randomly distributed but often concentrated in microscopically visible and functionally distinct inclusion bodies. How misfolded proteins are organized into these compartments, however, is still unknown. We have recently begun to investigate stress-inducible protein quality control (PQC) bodies in yeast cells. Surprisingly, we found that protein misfolding and aggregation were not sufficient to trigger body formation under mild heat stress conditions. Rather, compartment assembly also required the concerted action of molecular chaperones, protein-sorting factors and protein-sequestration factors, thus defining a minimal machinery for spatial PQC. Expression of this machinery was limited to times of acute stress through rapid changes in mRNA abundance and a proteasomal feedback mechanism. These findings demonstrate that yeast cells can control the amount of soluble misfolded proteins through regulated phase transitions in the cytoplasm, thus allowing them to rapidly adapt to changing environmental conditions.

Figure 1. A model for the coordinated action of sorting factors and molecular chaperones during acute heat stress. (A) Yeast cells growing under normal conditions, (B) cells exposed to acute heat stress and (C) cells that are recovering from stress. The events that induce sorting (association with a factor or assembly into an amyloid structure) are indicated in red. A bound misfolded protein is depicted in blue. Please note that only the complexes containing Btn2 are involved in aggregate sorting, while the Cur1 complex mediates sorting of Sis1 to the nucleus. See text for more details.