Figure 2.

Common upstream signaling pathways of autophagy and apoptosis under ER stress and the mechanisms of autophagy involved in determining cell fate under different intensities of ER stress.

Notes: Under ER stress, the unfolded protein response is activated, resulting in activation of PERK and phosphorylation of eIF2α. Selective induction of ATF4 occurs, which can promote the transcription of genes involved in autophagy, apoptosis, molecule chaperoning, ER-associated degradation, and metabolism. Moreover, ATF4 can also activate apoptosis via degradation of XIAP and cooperation with CHOP under prolonged ER stress. IRE1 activates XBP1, ASK1, and molecules downstream of JNK that promote autophagy and apoptosis. Through XBP1 and CHOP, ATF6 can indirectly regulate autophagy or apoptosis. Thus, the effects of ER stress-induced autophagy on cell survival have dual roles including pro-survival and pro-death. On one hand, autophagy can inhibit apoptosis through clearing misfolded/unfolded proteins and damaged organelles and inhibiting or degrading caspases, resulting in protecting cells from damages induced by ER stress. On the other hand, autophagy can serve as a platform for caspase-8 activation and degrade IAPs, which amplifies cell injury induced by ER stress.

Abbreviations: ER, endoplasmic reticulum; TMZ, temozolomide.