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. 2019 Feb 16;20(4):857. doi: 10.3390/ijms20040857

Figure 3.

Figure 3

Apoptotic signaling during ER stress. Prolonged or severe ER stress conditions induce apoptotic signaling through the activation of IRE1 and PERK pathways. Upon activation of the IRE1 pathway, IRE1 recruits TRAF2 and ASK1 on the ER membrane and this induces the apoptotic response upon modulation of the balance between proapoptotic and antiapoptotic genes. Furthermore, IRE1 digests specific miRNAs through its endoribonuclease domain (IRE1-dependent decay of mRNA, RIDD). PERK pathway activates ATF4, which in turn enhances the transcription of CHOP, a transcription factor responsible for the regulation of many proapoptotic genes (i.e., GADD34, ERO1, DR5, TRB3, Bcl-2 family genes). In this complex scenario, GADD34 and PP1 promote the dephosphorylation of eIF2α, leading to enhanced protein synthesis and the increase of protein load into the ER.