A screen for mutants requiring activation of the unfolded protein response for viability

The unfolded protein response (UPR) is an intracellular signal transduction pathway that monitors endoplasmic reticulum (ER) homeostasis. Activation of the UPR is required to alleviate the effects of ER stress. However, our understanding of what physiologically constitutes ER stress or disequilibrium is incomplete. The current view suggests that stress manifests as the functional capacity of the ER becomes limiting. To uncover the range of functions under the purview of the UPR, we previously devised a method to isolate mutants that (1) activate the UPR and (2) require UPR activation for viability. These mutants that represent functions, when compromised, cause specific forms of disequilibrium perceived by the UPR. Making UPR activation essential to these mutants ensures a stringent physiological link and avoids stimuli causing nonproductive UPR activation. Thus far, the screen has revealed that the range of functions monitored is surprisingly diverse. Beyond the importance of the screen to understand UPR physiology, it has proven to be useful in discovering new genes in many aspects of protein biosynthesis and quality control.