Abstract
The quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remained unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.
Highlights
Protein quality control (QC) pathways operate in all compartments of eukaryotic cells to eliminate misfolded proteins, the accumulation of which correlates with various age-onset diseases [1,2,3]
In wild-type (WT), Ste6 c was rapidly degraded by cytosolic QC (CytoQC) with only 30% of the substrate remaining at 12 min post-labeling (Fig 1A)
CytoQC was significantly slower in rpn11S119F, Δubp6, Δubp3, Δubp8, Δubp10 and Δdoa4 and moderately slower in Δubp2, Δubp14, Δotu2 and Δubp1 (Fig 1A and S3A Fig in S1 File)
Summary
Protein quality control (QC) pathways operate in all compartments of eukaryotic cells to eliminate misfolded proteins, the accumulation of which correlates with various age-onset diseases [1,2,3]. In cytosolic QC (CytoQC), chaperones bind misfolded proteins to inhibit aggregation and assist with refolding [4]. Substrates which fail to refold, such as Ste c and ΔssPrA, are degraded by the ubiquitin-proteasome system (UPS) [5,6,7]. Since many chaperones shuttle between the cytosol and the nucleus, misfolded cytosolic proteins can be ferried into the nucleus to be degraded by the nuclear UPS [S1 Fig in S1 File and 8, 9]. In the endoplasmic reticulum (ER), proteins which misfold in their luminal, transmembrane, or cytosolic domains are engaged by respective ER-associated degradation (ERAD) systems, ERAD-L, ERAD-M and ERAD-C [11], and are retro-translocated into the cytosol for degradation by the UPS [S1 Fig in S1 File and 12]. The model substrates of ERAD include CPY , Sec and Ste6 [11, 13,14,15]
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