The activation of the UPR is largely mediated by three innate stress sensors (Figure ): inositolrequiring enzyme-1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6) . Under basal conditions, a ubiquitous inhibitor of UPR activation, BiP, binds these three sensors and maintains their inactivated conformation . BiP's main function is as a chaperone to promote the productive folding of nascent polypeptides as they enter the ER. Under conditions of ER stress, with increased intralumenal concentrations of misfolded proteins in the ER, BiP preferentially binds to the exposed hydrophobic residues of these misfolded proteins, thereby allowing the three UPR sensors to activate and affect their downstream pathways to restore ER homeostasis . It has also been suggested that in addition to the dissociation of BiP from the UPR sensors, direct interactions between unfolded proteins and the UPR sensors are required as a second regulatory step in this process . Partial activation of the UPR could then be attributed to direct interactions of unfolded proteins with UPR sensors, or as a result of selective activation of the stress sensor(s) with the weakest affinity for BiP that are activated under low stress .