Fig. 1

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) initiation. Properly folded proteins (Green arrows) are processed at the Golgi apparatus and then translocated to their destination sites. Misfolded proteins (Red arrows) are retained in the ER lumen and are degraded by the ER-associated protein degradation machinery (ERAD). Under certain pathological situations misfolded proteins aggregate and accumulate into the ER lumen triggering a condition called ER stress (Blue arrows). In response to ER stress, the cell activates the Unfolded Protein Response (UPR), in which accumulated misfolded proteins are sensed by inositol-requiring enzyme 1 (IRE1), activating factor 6 (ATF6) and protein kinase R-like endoplasmic reticulum kinase (PERK) proteins. IRE1 protein dimerises, auto-phosphorylates and activates its endoribonuclease activity, which removes a small intron of the transcription factor X-box-binding protein 1 (XBP1u) that is then converted in XBP1s which acts as a transcriptional activator. ATF6 is cleaved and activated in the Golgi apparatus to yield a transcription factor (ATF6c) that migrates to the nucleus where activates the transcription of UPR target genes. PERK also dimerises and phosphorylates the eukaryotic translation initiation 2α (eIF2α), which attenuates most translation but stimulates translation of the transcription factor ATF4, which in turn activates genes to protect cells against the ER stress. The UPR signalling consists of four mechanisms: i) decreased translation to prevent further misfolded protein accumulation; ii) induction of ER chaperones to increase folding capacity; iii) induction of ERAD genes to increase degradation of misfolded proteins and iv) induction of apoptosis to remove stressed cells