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A Stress-Induced Pathway for the Degradation of Misfolded Proteins in S. cerevisiae

Szórádi, Tamás

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Abstract

The integrity of the proteome is fundamental for cell viability. Proteins can misfold due to genetic mutations or environmental stress. These misfolded proteins have a high tendency to accumulate as toxic protein aggregates which are associated with several well-known pathologies like Alzheimer’s, Huntington’s or Parkinson’s disease. To prevent protein misfolding, cells have evolved several protein quality control mechanisms that monitor and preserve the integrity of the proteome. In this PhD thesis we have uncovered and characterized a stress-inducible protein degradation pathway in budding yeast (Saccharomyces cerevisiae) that targets misfolded but also native proteins in the cytosol and the endoplasmic reticulum (ER) membrane for degradation. We employed an ER membrane-anchored reporter protein harbouring a misfolded cytosolic domain that was selectively degraded by the proteasome under stress conditions. A genetic screen, performed prior to the start of the PhD project, found the ubiquitin E3 ligase Ubr1, the serine protease Ynm3 and an uncharacterized protein (Yjl144W, named Roq1 by us) to be required for the stressinduced degradation of this misfolded model substrate. The three identified proteins act together in novel a linear protein degradation pathway, which we termed Stressinduced Homeostatically Regulated Degradation (SHRED). Mechanistic analysis elucidated that the ROQ1 gene is transcriptionally upregulated during various stresses. The resulting Roq1 protein is cleaved by Ynm3, which uncovers a positively charged arginine residue on its N-terminus. Subsequently, cleaved Roq1 through its new Nterminus interacts with Ubr1 and modulates its substrate specificity. Modified substrate recognition by Ubr1 enhances the proteasomal degradation of certain cytosolic and ER membrane proteins. Furthermore, a genetic screen and mass spectrometry analysis revealed endogenous candidate substrates of SHRED proposing that this pathway is not only implicated in quality control but also in quantity control of proteins.

Item Type: Dissertation
Supervisor: Knop, Prof. Dr. Michael
Date of thesis defense: 5 June 2018
Date Deposited: 20 Jun 2018 08:35
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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