UCSF

Disruption of protein folding homeostasis in the endoplasmic reticulum activates a signaling pathway termed the unfolded protein response, or UPR, which can mediate cell recovery or apoptosis. Understanding how the decision to live or die is made by the UPR is integral to affecting the outcome of ER stress-related pathologies. In cases of unwanted cell proliferation, inhibiting the cytoprotective branches of the UPR has shown promise in controlling cell populations. However, for cases of unwanted cell death, developing strategies to inhibit pro-apoptotic signaling of the UPR requires a deep, mechanistic understanding of the molecular events that commit the cell to an untimely fate. Chapter 1 gives an overview of both cytoprotective signaling and pro-apoptotic mechanisms of the UPR that pinpoint Death Receptor 5 (DR5) as a key driver of cell death. Chapter 2 provides published experimental evidence that reaffirms the role of DR5 in ER stress-induced apoptosis. Chapter 3 describes the experiments that demonstrate that apoptosis is driven by the direct interaction between DR5 and the source of ER stress, which is misfolded protein. In this way, DR5 assumes a terminal quality control pathway to detect unresolved protein folding stress along the secretory pathway and commit apoptosis to mitigate the consequences of secreting or displaying dysfunctional proteins.