Fig. 2: ERS-induced apoptosis.
From: Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment
ERS triggers the molecular cascade of apoptosis through the PERK, IRE1, and ATF6 pathways. Under ERS conditions, the IRE1 pathway is activated through the kinase domain of IRE1, which recruits and binds TRAF2 to initiate the ASK1-JNK/p38 MAPK signaling cascade. This leads to phosphorylation of Bcl-2 (inhibiting its anti-apoptotic function) and activation of the pro-apoptotic protein Bim. Simultaneously, IRE1 degrades survival factor mRNAs via the RIDD mechanism, collectively promoting apoptosis. In the PERK pathway, ERS induces PERK-mediated phosphorylation of eIF2α, enabling selective translation of ATF4. ATF4 then translocates to the nucleus and upregulates CHOP expression, which promotes pro-apoptotic molecules such as Bim and PUMA while suppressing Bcl-2, ultimately initiating the caspase cascade. The ATF6 pathway involves its proteolytic cleavage (generating ATF6-50), which regulates CHOP and death receptor DR5 (TRAIL Receptor-2) expression, thereby activating the caspase-8-dependent extrinsic apoptotic pathway. These three pathways are not independent but exhibit crosstalk and synergistic regulation through key nodes such as CHOP and apoptosis-related proteins, collectively determining the cellular fate between survival and apoptosis under ERS conditions. ER endoplasmic reticulum; PERK protein kinase RNA-like endoplasmic reticulum kinase, IRE1 inositol requiring enzyme 1, AFT6 transcription factor 6. Created with BioRender.com.
