FIGURE 1.

Schematic representation of the unfolded protein response (UPR). In case of ER stress (due to viral infection, metabolic impairments, inflammation, cancer, hypoxia, etc.) translated proteins improperly folded are recognized by the endoplasmic reticulum (ER) chaperon GRP78. This protein is usually bound to three ER receptors (PERK, IRE-1α, and ATF6), which are maintained in an inactive form. When GRP78 binds to unfolded proteins it releases these three receptors, which are activated either through dimerization and auto-phosphorilation (PERK and IRE-1α) or by translocation and cleavage (through SP1 and SP2 proteases) on Golgi apparatus membrane (ATF6). The PERK-controlled pathway is mainly deputed to the control of translational activity in the ER through EIF2α phosphorilation, but has also an active role in transcriptional control by regulating ATF4 translation. IRE-1α and ATF6, together with ATF4, have an important role in the transcriptional control of genes involved in UPR regulated processes such as apoptosis, autophagy, inflammation, and angiogenesis, etc. IRE-1α regulates XBP1 activity by modulating its RNA-splicing.