The endoplasmic reticulum (ER) is the first organelle that proteins of the secretory pathway encounter as they mature structurally and fold to their native conformations (Gething and Sambrook, 1990). Cells specialized for secretion, such as insulin-producing pancreatic islet β-cells, accommodate a high rate of cargo proteins transiting through the ER (Scheuner and Kaufman, 2008). But when conditions demand that these cells further increase protein secretion, the secretory pathway can quickly become overwhelmed. Inability to properly fold large secretory loads causes accumulation of unfolded proteins within the ER. In cells experiencing such “ER stress,” intracellular signaling pathways termed the unfolded protein response (UPR) become activated. Upon detecting unfolded proteins, three ER transmembrane sensors—IRE1α, PERK, and ATF6—initiate the UPR pathways (Harding et al., 1999; Tirasophon et al., 1998; Yoshida et al., 1998). Combinatorial signals from the three sensors increase transcription of target genes encoding ER chaperones and enzymatic activities, thus enhancing folding and maturation of secretory proteins. UPR targets also allow unfolded proteins to be extracted from the ER, and subsequently degraded in the cytosol (a process called ER-associated degradation) (Vembar and
