Fig. 1

Schematic diagram depicts the three branches of the unfolded protein response (UPR) and resulting downstream targets reviewed in the context of aging and retinal disease. Each branch is activated when the resident ER chaperone, GRP78, releases from IRE1, PERK, and ATF6 to bind accumulated unfolded or misfolded proteins. The resultant signaling cascades activate downstream effectors, such as XBP1 and ATF4, in an attempt to re-establish homeostasis through multiple means including repressing protein translation, promoting ERAD (endoplasmic reticulum associated protein degradation) and RIDD (regulated IRE1-dependent decay of mRNA), and upregulating the expression of ER chaperones and foldases. In addition, the UPR pathways regulates genes involved in a broad range of ER stress-dependent and independent cellular processes including autophagy, glucose metabolism, lipid synthesis, cytoskeletal reorganization, and calcium regulation