Signal transduction events associated with ER stress and UPR. Upon accumulation of unfolded or misfolded proteins in the ER three major ER stress sensors, PERK, ATF6 and IRE1, are activated following their dissociation from the ER chaperone GRP78. Activated PERK phosphorylates eukaryotic initiation factor 2α (eIF2α), which suppresses global mRNA translation but activates ATF4 translation. ATF4 translocates to the nucleus and induces the transcription of genes required to restore ER homeostasis. Activation of PERK also leads to the induction of CHOP (C/EBP homologous protein), which is involved in pro-apoptotic signaling. ATF6 is activated by proteolysis mediated by proteases S1P and S2P after its translocation from the ER to the Golgi apparatus. Active ATF6 translocates to the nucleus and regulates the expression of ER chaperones and X box-binding protein 1 (XBP1) to facilitate protein folding, secretion, and degradation in the ER. Xbp1 mRNA undergoes unconventional mRNA splicing carried out by IRE1. Spliced XBP1 protein (sXBP1) translocates to the nucleus and controls the transcription of chaperones, the co-chaperones and the PERK-inhibitor P58IPK, as well as genes involved in protein degradation.