Understanding how cell stress pathways contribute to defense responses in healthy cells

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This proposal examines how components of the Unfolded Protein Response (UPR) contribute to the molecular signaling pathways initiated to facilitate defense responses in healthy cells. The unfolded protein response (UPR) is a highly conserved stress response pathway activated in cells by accumulation of unfolded or misfolded proteins, a condition referred to as Endoplasmic Reticulum (ER) stress. The UPR is the collective term given to a series of orchestrated signaling pathways controlled by three ER anchored transmembrane receptors (IRE1, PERK and ATF6). Classically, these signaling mechanisms function to reduce levels of unfolded proteins and restore ER homeostasis. If that is not possible, signaling switches from pro-survival to pro-death and ER stress-induced cell death ensues. We are now beginning to realize components of the UPR pathway also influence signaling pathways essential to maintain cell viability including cellular defense processes. Like the UPR, inflammation can also be viewed as a mechanism aimed at restoring cellular homeostasis. However, in the case of inflammation the originating triggers (external or internal) indirectly cause a loss of cellular homeostasis, which is detected by internal mechanisms and leads to the activation of stress responses. For example, my recent work has defined a role for IRE1 in promoting structural assembly of the NLRP3 inflammasome a key cellular defense component. This research program investigates how cellular stress and defense signaling pathways integrate and work in a co-operative manner to insure the maintenance of cell viability. To this end, cellular reporter systems will be developed for IRE1, PERK and ATF6 allowing us to monitor their activation in healthy cells following initiation of cellular defense mechanisms. Using cell biology techniques, we will selectively block each arm of the UPR and assess the outcome of this on the ability of healthy cells to respond to internal or external threats. In addition to these broader questions addressing the interplay between stress and defense pathways, we will determine which signaling pathways contribute to IRE1-mediated regulation of the inflammasome and assess the importance of this in cell defense responses. This research program addresses the interplay between two fundamental cellular signaling pathways previously thought to act in independent and distinct manners. As such it represents a new emerging area of research at the intersection of cell biology and immunology. Knowledge generated from this program will greatly enhance our understanding of how healthy cells respond to challenges in their environment.