ER Stress and Apoptosis: A New Mechanism for Retinal Cell Death

Figure 1

Signaling pathways of the UPR. Accumulation of unfolded proteins in ER lumen results in the ER stress. In response to ER stress, Bip dissociates from ER stress transducers and binds to unfolded and misfolded proteins, resulting in the activation of ER stress transducers- IRE1, PERK and ATF6. Upon activation, IRE1 splices the mRNA of XBP1, and produces an active transcription factor named spliced XBP1 (XBP1-S), which upregulates ER chaperones and proteins implicated in the ER-associated protein degradation (ERAD). In addition, IRE1 recruits TRAF2 and ASK1, resulting in JNK activation. The activation of PERK increases phosphorylation of eIF2α, leading to a global attenuation of protein synthesis and a concomitant increase in ATF4 translation. In turn, ATF4 induces CHOP, a proapoptotic transcription factor. After the dissociation of Bip, ATF6 translocates to Golgi apparatus, where it is activated by proteolysis. Activated ATF6 transcriptionally induces ERAD genes and upregulates CHOP expression.