The Impact of Arsenic on Protein Homeostasis and Aggregation in Saccharomyces cerevisiae

Abstract

Arsenic and cadmium are two toxic heavy metals that occur naturally in bedrock. Arsenic is found in high concentrations in certain areas and can contaminate groundwater, leading to exposure through drinking water and crop irrigation for the local population. Cadmium is primarily dispersed in the environment with fertilizers and as a byproduct of the electronics industry, and it is absorbed by the body through food and cigarette smoke. Long-term exposure to these heavy metals is associated with cardiovascular diseases, cancer, diabetes and neurodegenerative diseases. One of the primary reasons for their toxicity is their ability to interact with proteins in cells, essential for normal cellular function. This leads to protein misfolding and aggregation, and disruption of cellular processes. We used the yeast Saccharomyces cerevisiae to better understand how these toxic substances affect cells. The first article demonstrates how yeast cells mobilize specific control pathways to varying degrees to manage protein homeostasis and eliminate arsenic stress. The second article focuses on the roles of chaperones and ubiquitin ligases in maintaining protein balance under arsenic stress. We show that the ubiquitin-proteasome pathway is the major player in preventing and eliminating arsenite-induced protein aggregates. The third article shows that arsenite and cadmium alter the formation and structure of alpha-synuclein amyloid fibers, as well as cause changes in the protein's cellular localization. The final study provides a proteome-wide analysis of arsenic-binding proteins and demonstrates that nuclear transport is a direct target of arsenite-induced proteotoxicity. Together, these studies offer a comprehensive insight into the mechanisms by which arsenite disrupts protein homeostasis - from interactions with proteins to aggregate management mechanisms. This dissertation aims to deepen our understanding of cellular responses to heavy metal exposure, hopefully with implications for future therapeutic strategies against metal-related diseases.