Figure 3

Schematic representation of the main UPR mechanisms, focusing on PERK related pathways. Upon accumulation of misfolded proteins in the ER lumen, chaperones such as BiP are displaced from the ER stress sensors PERK, IRE1 and ATF6, resulting in their activation. Upon phospohorylation, PERK assembles in a homodimer (active form), which phosphorylates EIF2α, initiating the downstream UPR response, that reduces the protein overload to the ER: 1) reduction of protein translation and 2) activation of ATF4 and other transcription factors including ATF3 and CHOP, resulting in a variety of cellular and biological effects. ATF3 and CHOP are also involved in a regulatory feedback control of PERK-EIF2α dependent on GADD34. PERK also regulates ATF6, which induces the expression of chaperones, such as BiP and ERp72, which are essentiel in protein processing and quality control. Misfolded proteins are then dissociated by retrotranslocation to the cytosol and degradation by the ubiquitine/proteasome complex (ER associated degradation, or ERAD).