Thiol-Based Misfolding: Linking Redox Balance to Cytosolic Proteostasis

<p>The eukaryotic cytosolic proteome is vulnerable to changes in proteostatic and redox balance caused by temperature, pH, oxidants and xenobiotics. Cysteine-containing proteins are especially at risk as the thiol side chain is subject to oxidation, adduction and chelation by thiol-reactive compounds. All of these thiol-modifiers have been demonstrated to induce the heat shock response and recruit protein chaperones to sites of presumed protein aggregation in the budding yeast <em>Saccharomyces cerevisiae</em>. However, endogenous targets of thiol stress toxicity responsible for these outcomes are largely unknown. Furthermore, I hypothesize proteins identified as redox-active are prone to misfolding and aggregation by thiol-specific stress. Perhaps these redox-sensitive proteins are those unknown targets. My work has determined that changes in cytosolic redox balance via thiol-specific stresses including cadmium, diamide, and glucose starvation are proteotoxic by monitoring aggregation of an endogenous redox-sensitive model protein. Emerging from the ribosome, newly synthesized cysteine-containing peptides are in a reduced state. Exposure to thiol-specific stress results in the modification of protein thiols by covalent interactions and oxidation. These non-native modifications to proteins result in an inability to properly fold, leading to the formation of protein aggregates. The thiol-reactive stress and subsequent aggregation is sensed by the cytoplasmic protein quality control network that activates stress responses and recruits chaperones such as Hsp104 and Tsa1. These chaperones assist in clearing existing aggregates and preventing further damage. Above all, protein aggregation as a result of exposure to thiol-specific stress extends to human cells, thus establishing a conserved mechanism and model for redox-associated proteostasis.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• Amy, Ford
• <p>https://orcid.org/0000-0002-1394-0128</p>

Contributors dc:contributor

• Kevin A. Morano
• Theresa M. Koehler
• Ambro van Hoof

• chaperone
• oxidative stress
• proteostasis
• reactive oxygen species
• redox
• signaling
• thiol-reactivity
• protein aggregation
• Biology
• Cell Biology
• Laboratory and Basic Science Research
• Molecular Biology
• Molecular Genetics
• Other Microbiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/928

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1973