The role of stress-induced increases in SUMO2/3 conjugation during the Heat Shock Response (HSR) has remained enigmatic. We investigated SUMO signal transduction at the proteomic and functional level during the HSR in the context of cells depleted of proteostasis network components via chronic Heat Shock Factor 1 inhibition versus cells with normal pro-teostasis networks. In the recovery phase post-heat shock, SUMO2/3 conjugation remained high for a prolonged time in cells lacking sufficient chaperones. Similar results were obtained upon inhibiting HSP90, indicating that increased chaperone activity during the HSR is critical for the recovery of SUMO2/3 levels post-heat shock. Proteasome inhibition during the re-covery phase likewise prolonged SUMO2/3 conjugation, indicating that stress-induced SU-MO2/3 targets are subsequently degraded by the ubiquitin-proteasome system. Functionally, we show that SUMOylation profoundly enhances solubility of target proteins upon heat shock in vitro. Collectively, our results implicate SUMO2/3 as a rapid response factor protecting the proteome from aggregation upon proteotoxic stress.