The unfolded protein response (UPR) results in the inhibition of translation, facilitated protein degradation and production of ER chaperones and other molecules that restore the ER folding environment. These activities are signaled through three UPR sensors—PERK, IRE1a and ATF6—that mediate the canonical response pathways. PERK phosphorylates eIF2a to attenuate general protein translation. It can also regulate the activity of several transcription factors such as ATF4, ATF3 and nuclear factor E2–related factor-2 (Nrf2). Upon autophosphorylation, the RNase activity of IRE1a results in the production of spliced and active XBP-1, leading to the expression and production of ER chaperones and components of the ER-associated degradation (ERAD) process. ATF6 moves to the Golgi apparatus, where it is proteolytically processed to generate an active transcription factor (ATF6(N)) that stimulates the expression of chaperones and XBP-1. There may be additional and unknown aspects of UPR, especially related to the sensing of nutrients and mediation of metabolic adaptations. ERO1, endoplasmic reticulum oxidoreduction-1.