Schematic diagram of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, signals are transmitted from the ER to the cytoplasm via 3 transmembrane proteins in the ER membrane. Signaling from these 3 proteins leads to many downstream responses: Protein kinase RNA (PKR)-like ER kinase (PERK) phosphorylates elF2, which causes a global decrease in protein synthesis. IRE1 activation leads to splicing of XBP1; sXBP1 enters the nucleus and increases transcription of chaperone proteins, ER-associated protein degradation proteins, and proapoptotic proteins. ATF6 is cleaved and the cleaved portion enters the nucleus where it stimulates transcription of XBP1 and other unfolded protein response target genes.