Figure 1.

Unfolded protein response pathways are shown. The newly synthesized protein destined for modification in ER enters through SEC61 channel and undergoes folding and maturation. Under basal/unstressed conditions, the BIP (immunoglobulin heavy chain binding protein) binds to ATF6 (activating transcription factor 6), IRE1α (inositol-requiring kinase 1), and PERK [double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase] thereby inhibiting them. During ER stress, BIP dissociates from the three UPR sensors and binds to unfolded/misfolded proteins, thus initiating adaptive signaling events to help ER recover from the stress. Dissociation of BIP from ATF6 unmasks a Golgi-localization signal (GLS, not shown here), which facilitates its translocation to Golgi where it undergoes regulated intramembrane proteolysis (RIP) by resident proteases, Site-1 protease (S1P) and Site-2 protease (S2P). The released ATF6 acts as a transcription factor, which travels to the nucleus and binds to ER-stress response elements (ERSE) and induces transcription of several genes, including BIP, CHOP (CCAAT/enhancer-binding protein homologous protein), and X-box-binding protein 1 (XBP1). Similarly IRE1α is activated and undergoes homodimerization and autophosphorylation, thereby activating the endoribonuclease activity, which splices XBP1 mRNA to spliced XBP1 mRNA, which codes for a transcription factor XBP1s that translocates to nucleus and regulates genes involved in UPR and ER-associated degradation (ERAD). Finally, the release of BIP activates PERK pathway, which initiates a global translational arrest by phosphorylating the translation initiation factor 2α (EIF2α), thus decreasing ER protein load. ATF4 (Activating Transcription Factor 4) mRNA escapes translational suppression exclusively as it possesses internal ribosome entry site (IRES) sequences in the 5′-untranslated regions. ATF4 enters nucleus and regulates expression of UPR target genes.