A Nucleus-based Quality Control Mechanism for Cytosolic Proteins

Abstract

Mechanisms that monitor the folding states of polypeptides are found throughout the cell. In the cytosol, how misfolded proteins are recognized and degraded is poorly understood. Here, misfolded proteins are shown to traffic to the nucleus where they are ubiquitinated by the San1p E3 ubiquitin ligase and degraded by the 26S proteasome.

Firefly luciferase mutants as sensors of proteome stress

“…The hypothesis is in line with a study in yeast which showed that degradation of cytosolic misfolded carboxypeptidase Y (CPY*) occurs in the nucleus (Prasad et al, 2010). To understand if the cellular localization of the protein has an influence on its degradation, we measured the degradation kinetics of NES-FlucDM-EGFP in the nucleus, by performing a cycloheximide (CHX) chase experiment in the presence of an inhibitor of nuclear export.…”

“…The results presented in Figure 47 as well as findings using CPY* in yeast (Prasad et al, 2010) suggest a model, where misfolded cytosolic proteins move to the nucleus for their degradation. This model would predict that some cellular factor can recognize these misfolded proteins in the cytosol and direct them to the nucleus for degradation.…”

“…Interestingly, it was demonstrated in S. cerevisiae that the terminally misfolded cytosolic protein, mutant carboxypeptidase Y without signal sequence (ΔssCPY*), migrates into the nucleus and is selectively ubiquitinated by a nuclear E3 ligase called San1p for degradation by the UPS (Prasad et al, 2010). It is therefore possible that some destabilized proteins in the cytoplasm are recognized and selectively targeted to the nucleus for UPS mediated degradation.…”

Intracellular Dynamics of the Ubiquitin-Proteasome-System

“…Through these non-invasive techniques, the localization of the proteasome in growing yeast and highly proliferating cancer cells has been elucidated to be primarily nuclear ( Enenkel et al , 1998; Laporte et al , 2008; McDonald & Byers, 1997; Russell et al , 1999). In line with this finding, increasing evidence in the literature suggests that certain misfolded proteins are imported from the cytoplasm into the nucleus solely for proteasomal degradation ( Park et al , 2013; Prasad et al , 2010). Conversely, transient nuclear proteins are exported into the cytoplasm for proteolysis, indicating a dynamic shift of proteasomal substrates between the nucleus and cytoplasm ( Chen & Madura, 2014a).…”

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…The latter, however, would imply that these proteins are actively imported as a result of the inhibition of their original function and thus were marked for protein degradation. Indeed, recent studies provide compelling evidence that cytosolic misfolded proteins are actively imported into the nucleus for proteasomal degradation (Prasad et al 2010;Park et al 2013;Shibata and Morimoto 2014). Having found that the major fraction of 20S proteasomes is located in nuclei of both placebo-and propiverinetreated F344 rats and that the BioGRID interaction database provides evidence that DAAO interacts with KLHL42, a substrate-specific adapter of an E3 ubiquitin-protein ligase, 1 we wanted to demonstrate that proteins, e.g., DAAO and catalase are imported into the nucleus for proteasomal degradation.…”