FIGURE 3.

Unfolded protein response in the ER leads to ER stress. The accumulation of protein aggregates is sensed by three ER-stress transducers: IRE1α, PERK, and ATF6. ER stress causes IRE1α dimerisation, which activates its intrinsic RNAse activity and leads to alternative splicing of XBP1 mRNA. Spliced XBP1 forms a functional transcription factor. XBP1 increases expression of chaperone related genes and those involved in ERAD. PERK also dimerises due to ER stress. PERK dimerization leads to phosphorylation of the eukaryotic initiation factor eIF2α, thus inhibiting general protein synthesis. Inhibition of protein synthesis allows the translation of stress response transcription factor, ATF4. ATF4 increases expression of genes related to autophagy and apoptosis. Via the action of coat protein complex II (COPII), ATF6 translocates from the ER membrane to the Golgi during ER stress where it is processed by the Site 1 (Sp1) and Site 2 (Sp2) proteases. Cleavage produces a functional cytosolic fragment of ATF6. The ATF6 transcription factor induces expression of genes related to ERAD, but also XBP1, thereby promoting UPR. Chronic ER stress and UPR activation indicates the cell has failed to respond to ER stress. Under such conditions all three ER stress transducers lead to the increased expression of CHOP, which promotes apoptosis. For further details please refer to the main text.