Heat-induced degrons and the co-chaperone Ydj1-adaptor mediate the ubiquitination of misfolded proteins by the Rsp5 ubiquitin ligase upon stress (558.1)

The ubiquitin proteasome system is critical for the prompt elimination of misfolded proteins, which pose a deleterious risk to the cell. Indeed numerous diseases are associated with protein misfolding and aggregation. The heat-shock response mediates several cellular events to prevent accumulation of misfolded proteins including upregulation of heat-shock proteins and increased proteolysis. We found that upon heat-stress Rsp5 is the main E3 ligase that ubiquitinates cytosolic misfolded proteins to target them for proteasome degradation. Notably, degradation of misfolded proteins is dependent on both Ubp2 and Ubp3 deubiquitinases. The absence of either deubiquitinase leads to reduced cell fitness upon misfolding stresses. We also found that the association of Rsp5 with the Hsp40 co-chaperone Ydj1 increases upon stress and that association is required for the ubiquitination of heat-induced Rsp5 substrates. In addition, PY Rsp5-binding motifs are also enriched among heat-induced Rsp5 substrates and found pri...