Sequestrase chaperones protect against oxidative stress-induced protein aggregation and prion formation

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since no stress sensitivity has been reported in deletion mutants. We show here that Btn2 and Hsp42 are required for oxidant tolerance and act to sequestering misfolded proteins into defined PQC sites following ROS exposure. We have used the Sup35 translation termination factor as a model oxidized protein to show that protein aggregation is elevated and widespread in mutants lacking Btn2 and Hsp42. Oxidant-induced prion formation is also elevated in sequestrase mutants consistent with the idea that Btn2 and Hsp42 function to sequester oxidatively damaged Sup35, thus preventing templating to form its heritable prion form. Taken together, our data identify protein sequestration as key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.