The ensemble of molecular chaperones and proteases constitutes the cellular system that repairs and eliminates misfolded proteins. The activity of this system ensures not only the recovery of cells from protein-damaging stress conditions, but also the maintenance of protein homeostasis under normal growth conditions. The concomitant involvement of members of the Hsp70 and Hsp90 chaperone families in stress-related, regulatory, and housekeeping functions allows the integration of environmental stimuli into regulatory networks (4
). However, it has remained unclear whether other chaperones are also involved in regulatory processes.
One chaperone which so far has been connected only to stress-related protein quality functions is the oligomeric AAA+
chaperone Hsp104 of Saccharomyces cerevisiae
. Hsp104 is essential for the development of thermotolerance by reactivating aggregated proteins after severe stress conditions and for prion propagation by severing prion fibrils (31
). Yeast cells, when grown at 30°C, harbor approximately 5,000 copies of Hsp104 hexamers per cell, a number that is minor compared to other cytosolic chaperone machineries (e.g., Hsp70 and Hsp90) that are involved in general protein-folding events (10
). The known cellular functions of Hsp104, however, cannot provide a rationale for the determined Hsp104 levels, since protein aggregation is hardly detectable in yeast cells at 30°C even in mutant cells lacking Hsp104 function. Furthermore, yeast prions occur de novo at a very low rate of 10−6
per cell. In consequence, both well-characterized Hsp104 activities are barely required at 30°C, suggesting that Hsp104 has additional, so far unknown housekeeping functions. On the other hand, an S. cerevisiae hsp104
knockout exhibits no obvious phenotype at 30°C (27
), giving no clues to a potential involvement of Hsp104 in other cellular processes.
Recently, Hsp104 was demonstrated to influence the asymmetric distribution of oxidatively damaged (carbonylated) proteins (8
). It remained unclear whether the role of Hsp104 in this process relies on its known activities in protein quality control or on an unknown involvement in other cellular processes. Here, we provide evidence that Hsp104 is part of a network that controls the inheritance of damaged proteins under physiological growth conditions.