Research Paper Volume 5, Issue 11 pp 802—812

Figure 6. Schematic representation of how aggregated proteins might result in a negative proteostasis feedback loop. One of many cellular functions of the UPS is to degrade native (e.g. cell cycle regulators), damaged, or aberrant proteins. If the level of damaged proteins exceeds the proteasomal capacity or if UPS degradation is somehow compromised, protein aggregates will form. The disaggregase Hsp104 can together with Hsp70/40 resolve protein aggregates. However, if the accumulation of aggregated protein is too severe, as seen in aged cells, these may interfere with the proper function of the UPS creating a negative feedback loop. This study indicates that the buildup of aggregates in aged cells can be counteracted either by increasing the amount of proteasomes present by stabilizing Rpn4, through the deletion of UBR2, or by increasing the level of disaggregation through Hsp104 overproduction. [UPS=ubiquitin proteasome system; P^N= native protein; P^D= damaged protein P^agg.= aggregated proteins].