Secretory protein folding, modification and the unfolded protein response

Proteins entering the secretory pathway at the endoplasmic reticulum (ER) undergo a vast array of post-translational modifications some of which are essential for correct folding, assembly and secretion. Failure to fulfil these functions results in several diseases due to the lack of secretion of proteins such as insulin and antibodies, or due to cell death triggered by an unfolded protein stress response. The ER provides a unique environment for protein modifications such as disulfide formation and glycosylation. To ensure efficient protein folding and secretion the cell maintains the environment within the ER that ensures these processes occur efficiently and reacts to situations of cell stress. This proposal builds on exciting new observations from my group to dissect molecular mechanisms involved in secretory protein biogenesis. Our particular focus will be on how the cell maintains ER redox balance, how the repertoire of ER folding factors orchestrate correct protein folding and N-linked glycosylation and how the UPR sensor ATF6 is activated following proteotoxic stress. Our aims will be achieved using a combination of innovative new technological approaches and previously established robust assays to follow protein folding and assembly in both reconstituted and cellular systems.