Figure 1.

Overview of the unfolded protein response. Fluctuations in the unfolded protein load placed on the endoplasmic reticulum can give rise to transient imbalance between capacity and demand, which we refer to as ER stress. This elicits two major adaptations: attenuation of new protein synthesis (mediated by PERK and eIF2α phosphorylation), which rapidly decreases the load on the organelle; and induction of a gene expression program (effected by IRE1-mediated XBP1 splicing) that up-regulates the organelle’s capacity to deal with incoming proteins. Regulated translation is also coupled to changes in gene expression, as indicated by the horizontal arrow connecting the two outputs. Destabilization of mRNAs encoding secreted proteins by regulated IRE1-dependent degradation (RIDD) contributes to the relief of ER load. Because these adaptations can be elicited experimentally by manipulations that perturb protein folding in the ER, they came to be known as the ER unfolded protein response (UPR). For simplicity, the third mediator of the UPR, ATF6, is omitted from this diagram.