Research in the Sevier lab focuses on characterization of the signaling pathways that sense and respond to cellular redox imbalances to alleviate oxidative stress. Specifically, research efforts focus on how the cell maintains a redox environment in the endoplasmic reticulum (ER) lumen appropriate for oxidative protein folding. We study the molecular mechanisms regulating cellular oxidative folding and stress pathways using a combination of molecular, genetic, and biochemical techniques.
Normal cell function relies on an ability of the ER to efficiently fold proteins. The crucial role of protein folding for cellular function is underscored by the number of diseases associated with the defective maturation of ER-generated polypeptides (e.g. Cystic Fibrosis, Alzheimer's Disease, Diabetes). An essential step in the folding of many proteins within the ER lumen is the formation of disulfide bonds between cysteine residues. Intriguingly, this vital step for protein biogenesis in the ER is also a potentially significant source of detrimental reactive oxygen species (ROS). We would like to understand the complex systems that allow cells to balance the essential process of oxidative folding with potentially damaging ROS production. Maintaining a proper redox balance in the ER is key to maintain an environment for protein generation in the ER and to prevent oxidative stress. At present, our lab has uncovered two redox pathways that are required to maintain normal ROS physiology within the ER. Currently, we are focused on mechanistically defining these two uncharacterized systems.