SC COBRE in Oxidants, Redox Balance and Stress Signaling

Danyelle Townsend, Ph.D.

Danyelle Townsend, Ph.D.
Assistant Professor
Pharmaceutical and Biomedical Sciences

Ph.D., University of Virginia Medical School, 2001


ROS/RNS and the unfolded protein response

Low levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) can determine cell structure function relationships, particularly as mediators of critical signaling events. The co-opting of such chemistry for practical use by biological systems is one of the vagaries of natural selection and evolutionary adaptation. We propose to identify the molecular targets of ROS and RNS and define the pathways cellular defense systems have developed to cope with stress. Using this target information, we will unite mechanistic and translational studies and eventually improve clinical understanding of pathologies affected by ROS and RNS, goals that include drug discovery and development. Our preliminary data suggest that protein disulfide isomerase (PDI) is S-glutathionylated as a consequence of ROS/RNS exposure. Protein disulfide isomerase (PDI) is the most abundant protein in the endoplasmic reticulum (ER), catalyzing a complex series of oxidations and reductions that facilitate protein-folding processes. Three signaling pathways collectively referred to as the unfolded protein response (UPR) have evolved to ensure that misfolded or unfolded proteins do not accumulate. The specific cellular damage that leads to protein folding dysfunction is not defined; however, S-glutathionylation, which is an oxidative- and nitrosative-stress-induced post-translational addition of glutathione (GSH) to cysteine residues—and the S-glutathionylation of PDI in particular—may represent an important signaling event. S-glutathionylation of PDI may affect a number of the downstream effectors of the UPR pathway, the specific components of which have yet to be fully described. The susceptibility of target cysteine residues to ROS and RNS provide the conduit for linking these events. The hypothesis is that S-glutathionylation of PDI is an upstream signaling event that leads to the UPR, resulting in apoptosis.