Cross talk between redox regulation and protein quality control

The final stage of protein synthesis is protein folding and localization. Control over a healthy proteome begins with the birth of the polypeptide chain and ends with the coordinated death of the mature protein by degradation. One of the major players in eukaryotic protein degradation is the essential and highly conserved ATPase known as CDC48 in yeast (VCP/p97 in mammals). CDC48 serves as a shuttle bus, extracting and delivering misfolded proteins from membranes of the ER, mitochondria, and nucleolus and cytosol, to the proteasome for degradation.

Here I will present a study where we dissect the crosstalk between protein oxidation and protein quality control, by focusing on the role of CDC48 in maintaining cellular redox homeostasis during normal and proteotoxic stresses. We have identified a redox sensitive site in CDC48 which regulates CDC48’s localization and activity, maintaining “healthy” proteome during oxidative stress and chronological aging in yeast.

Moreover, I will describe a novel methodology to track redox status at single cell resolution, which allows to characterize a redox-based heterogeneity, using the redox-sensitive Grx1-roGFP2 probe. Application of this methodology enabled us to identify redox-associated factors, including CDC48, and demonstrate the degree to which individual proteins may influence the global redox status.