Redox Regulation and the Role of Oxidative Stress in Host Defense and Aging
Redox Regulation and the Role of Oxidative Stress in Host Defense and Aging
Many physiological (e.g., host defense, aging) and pathological conditions (e.g., neurodegenerative diseases, diabetes) are associated with the accumulation of reactive oxygen and reactive nitrogen species, a situation generally termed oxidative stress. One of the most sensitive and selective targets of reactive oxygen and nitrogen species in the cell are the thiol groups of proteins. The rapid rate of thiol oxidation in combination with its reversibility makes thiol groups ideal candidates for functional nano-switches in proteins. It is therefore not surprising that several proteins have been identified over the past few years that use thiol-based redox switches to control their protein activity. Many of these proteins have been now found to play active roles in the protection of cells and organisms against oxidative stress.
We have discovered Hsp33 as one of the first molecular chaperones that are specifically activated by reactive oxygen species conditions. We found Hsp33 to be the central player of a redox-regulated chaperone network that efficiently protects cells against the otherwise lethal consequences of oxidative stress. To gain detailed understanding of the mechanistic aspects of this redox regulation, we are conducting biochemical, spectroscopic and structural studies with the isolated proteins in vitro. To investigate the cytoprotective role that Hsp33 plays during oxidative stress in E. coli and the enteropathogenic Vibrio cholerae, we are applying cell biological and microbiological techniques. These studies will elucidate Hsp33’s potential role in host colonization and pathogenesis.
We utilized our knowledge about thiol-based redox switches to develop several innovative techniques to detect, quantify and monitor the extent of oxidative thiol modifications in cells and organisms. We are now applying these tools to investigate the role of oxidative stress conditions during aging in S. cerevisiae and Caenorhabditis elegans. We are using mass spectrometry based thiol trapping techniques(e.g., OxICAT) and oxidative stress sensing proteins to monitor when reactive oxygen species begin to exert their damaging cellular effects during the lifespan of the organism. Our studies will help us understand the molecular basis of aging and the role that oxidative stress plays in this process. They will have the potential to develop more efficient antioxidant therapies.
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