TSA1 to the rescue

Cell http://dx.doi.org/10.1016/j.cell.2016.05.006 (2016)

The failure to remove and degrade stress-induced protein aggregates by the Hsp70 chaperone and Hsp104 disaggregase has been associated with premature aging in yeast. However, it is not clear how Hsp70 and Hsp104 are recruited to these aggregates in times of oxidative or heat stress. Hanzén et al. performed a yeast synthetic lethal genetic screen and observed interactions of the yeast cytosolic peroxiredoxin Tsa1 with the protein quality-control system. Elevated dosage of Tsa1 promoted increased lifespan independent of caloric restriction and hydrogen peroxide (H₂O₂) scavenging and was associated with a low level of protein aggregates. The authors found that H₂O₂ promoted the direct recruitment of Hsp70 and Hsp104 to age-induced protein aggregates. This recruitment was facilitated by the hyperoxidation of Tsa1 at a specific cysteine residue by H₂O₂. TSA1 mutants showed rapid accumulation of protein aggregates and ubiquitinated proteins, resulting in premature aging. Hanzén et al. furthermore noted that the timing of aggregate clearance coincided with sulfiredoxin (Srx1)-mediated reduction of Tsa1. Consistent with this observation, srx1 mutants exhibited slower aggregate clearance, suggesting that Srx1-mediated reduction of Tsa1 is required to facilitate the removal of these aggregates. Overall, these findings propose a redox switch defense mechanism for maintaining proteostasis in aging cells and in response to H₂O₂ stress.