Endoplasmic Reticulum Stress-Related Factors Protect against Diabetic Retinopathy

Figure 2

In response to ER stress, Bip separates from the three transmembrane mediators, causing the unfolded protein response to be activated. Unbound PERK then phosphorylates eIF2α, leading both to inhibition of new protein translation and to induction of the ATF4 transcription factor. ATF4, in turn, activates CHOP gene expression, which then promotes apoptosis and induces the growth arrest and DNA damage-inducible gene 34 (GADD34). The GADD34 phosphatase dephosphorylates eIF2α, thereby completing a negative feedback loop. Meanwhile, the unbound IRE1 initiates splicing of the XBP-1 mRNA. Recruitment of the TNF receptor-associated factor3 (TRAF3) and apoptosis signal-regulating kinase 1 (ASK1) to IRE1 leads to activation of c-Jun amino-terminal kinase (JNK), which in turn activates c-Jun and mitogen-activated protein kinase (MAPK) and ultimately promotes CHOP activity. Unbound ATF6 is cleaved within the Golgi apparatus by the site-1 protease (S1P) and the site-2 protease (S2P) to produce an active transcription factor fragment known as ATF6-N, which in turn activates XBP1 and CHOP; in addition, transcription of ER chaperones and protein disulphide isomerase is increased.