Figure 4.

The Integrated Stress Response (ISR). The PERK pathway of the UPR is also a member of the ISR. Various stressors, including ER stress, amino acid deficiency, ultraviolet rays, heat, ROSs, and heme deficiency, can activate one or more of the four eIF2α kinases: PERK, HRI, GCN2, and PKR. The ISR hinges on eIF2α, which is phosphorylated by the four kinases. Phosphorylated eIF2α binds eIF2β, a key component of an essential complex involved in initiating protein translation, to inhibit global protein synthesis, except ATF4 and ATF4-regulated genes like CHOP. ATF4 positively regulates expression of cytoprotective genes, as well as upregulating CHOP, which can induce apoptosis under chronic ER stress conditions. Independent of the ISR, ER stress-induced activation of the PERK pathway can also enhance the anti-oxidant response by upregulating genes via the direct phosphorylation of nuclear factor erythroid 2-related factor (Nrf)2.