Fig. 5.

Redox regulation of apoptosis under ER stress. PERK can provoke apoptotic signaling by phosphorylating eIF2α, which stimulates the translation of ATF4. Acting as a transcription factor, ATF4 then promotes the transcription of CHOP/GADD153, which downregulates the anti-apoptotic protein Bcl-2 and upregulates the pro-apoptotic proteins BIM and PUMA. CHOP/GADD153 also transcriptionally induces ERO1 to produce ROS. Another apoptotic pathway is the JNK, which is activated by the IRE1α-TRAF2-ASK1 complex. Phosphorylated JNK activates the downstream apoptotic pathways, and induces oxidative stress related to mitochondria. In addition, the accumulation of misfolded proteins induced by ER stress will consume a large amount of GSH to induce oxidative stress. Moreover, calcium channel proteins IP₃R can be activated by SERCA, leading to calcium outflow which induces apoptosis.