Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy

Figure 1

The unfolded protein response in adaptive, apoptotic and redox responses. Upon accumulation of misfolded proteins in the ER, the release of BiP allows IRE1 and PERK to oligomerize. Oligomerized IRE1 disposes of an intrinsic endoribonuclease activity that mediates the unconventional splicing of XBP1mRNA which is subsequently translated into XBP1s, a potent transcription factor regulating expression of genes involved in ERAD and ER quality control. IRE1 signaling is positively regulated by binding of the multidomain proapoptotics Bax and Bak, while its activity is suppressed by the transmembrane protein BI-1. The interaction of Bax/Bak with IRE1 is required for the recruitment of TRAF2 and ASK1 leading to the activation of the MAPKs JNK and p38 MAPK, through specific MKKs. Oligomerized PERK phosphorylates the translation initiating factor eIF2𝛼, resulting in suppression of general protein translation while favoring the translation ATF4, which induces the expression of genes involved in restoring ER homeostasis. Phosphorylation of Nrf2 by PERK disrupts its association with Keap1 resulting in its nuclear accumulation and upregulation of genes associated with various antioxidant responses. In contrast to PERK and IRE1, release of BiP from ATF6 induces its translocation to the Golgi where its processing generates an active transcription factor. Cleaved ATF6 controls mainly genes involved in ERAD and ER homeostasis. Upon severe ER stress, ATF4, XBP1s, and ATF6 can upregulate the expression of the proapoptotic transcription factor CHOP, which mediates apoptosis by the upregulation of proapoptotic BH3-only protein Bim and by suppressing Bcl-2 expression. CHOP activity is enhanced through phosphorylation by p38MAPK. Phosphorylation by JNK in turn activates Bim while inhibiting Bcl-2 functions.