The unfolded protein response unfolds

Abstract

As a key organelle of protein targeting and secretion, the endoplasmic reticulum (ER) plays host to a wide variety of protein maturation steps including folding, modification, and complex formation. Homeostasis of ER function is therefore critical to cell function. The unfolded protein response (UPR), a conserved eukaryotic signal transduction pathway, regulates the ER's capacity to perform protein folding according to cellular demand. UPR signaling is initiated by ER transmembrane components that sense unfolded protein levels within the ER. In yeast, the only known UPR initiator is IRE1, a transmembrane serine/threonine kinase/endoribonuclease. In higher eukaryotes, the UPR also comprises signals initiated by the ER-transmembrane kinase PERK and the ER-transmembrane transcription factor ATF6. A major consequence of UPR initiator activation is transcription induction of a wide variety of genes for ER-resident chaperons and protein folding enzymes, in order to increase ER protein folding capacity. Ultimately, UPR activation leads to remodeling the entire secretory pathway in order to meet cellular demand. The identification of these initiators and recent studies of their behaviors is revealing fascinating aspects of the overall UPR. This review discusses highlights of these discoveries and relationships between the UPR signaling branches initiated by each ER component. © Springer-Verlag Berlin Heidelberg 2006.