Abstract
Elimination of misfolded proteins is crucial for proteostasis and to prevent proteinopathies. Nedd4/Rsp5 emerged as a major E3-ligase involved in multiple quality control pathways that target misfolded plasma membrane proteins, aggregated polypeptides and cytosolic heat-induced misfolded proteins for degradation. It remained unclear how in one case cytosolic heat-induced Rsp5 substrates are destined for proteasomal degradation, whereas other Rsp5 quality control substrates are otherwise directed to lysosomal degradation. Here we find that Ubp2 and Ubp3 deubiquitinases are required for the proteasomal degradation of cytosolic misfolded proteins targeted by Rsp5 after heat-shock (HS). The two deubiquitinases associate more with Rsp5 upon heat-stress to prevent the assembly of K63-linked ubiquitin on Rsp5 heat-induced substrates. This activity was required to promote the K48-mediated proteasomal degradation of Rsp5 HS-induced substrates. Our results indicate that ubiquitin chain editing is key to the cytosolic protein quality control under stress conditions.
Highlights
Elimination of misfolded proteins is crucial for proteostasis and to prevent proteinopathies
We discovered that yeast Ubp[2] and Ubp[3] are two deubiquitinases that promote proteasomal degradation of cytosolic misfolded proteins targeted by Rsp[5] after heat stress
Degradation of cytosolic misfolded proteins is likely controlled by both the action of protein quality control (PQC) E3 ligases and antagonizing deubiquitinases, which could prevent the proteolysis of transiently misfolded proteins
Summary
Elimination of misfolded proteins is crucial for proteostasis and to prevent proteinopathies. Rsp[5] is required to mediate the buildup of K48-linked poly-ubiquitin chains after HS14, consistent with its role in targeting these misfolded substrates to the proteasome[29] It remained unclear how Rsp[5] can promote the conjugation of non-K63 linkages, such as K48 chains, for the proteasomal degradation of cytosolic misfolded substrates upon HS. We discovered that yeast Ubp[2] and Ubp[3] are two deubiquitinases that promote proteasomal degradation of cytosolic misfolded proteins targeted by Rsp[5] after heat stress We found that these deubiquitinases prevent the assembly of K63linked ubiquitin chains to promote the buildup of K48-linked ubiquitin chains by Rsp[5], which displays altered linkage specificity under stress conditions
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