The Unfolded Protein Response and Diabetic Retinopathy

Figure 1

UPR signaling pathways in retinal cell physiology. Three ER stress sensors PERK, IRE1, and ATF6 are activated when unfolded proteins tether the ER chaperone BiP/GRP78 away from the sensors. Upon activation, IRE1 autophosphorylates and forms a dimer or oligomer that mediates the unconventional splicing of XBP1 mRNA. This process generates the active transcription factor XBP1s that regulates genes involved in ER-associated protein degradation (ERAD), autophagy, ER quality control, and redox homeostasis. Activated IRE1 recruits TRAF2 and induces activation of JNK and NF-κB leading to increase transcription of inflammatory genes. Once removed from BiP/GRP78, AFT6 moves to the Golgi where it is cleaved by local site 1 and site 2 protease. The cleaved ATF6 is a transcription factor that regulates a subset of components for ERAD and ER chaperones. Like IRE1, PERK is activated by autophosphorylation and phosphorylates the translation initiation factor eIF2α, which suppresses the general translation but selectively increases the translation of ATF4. ATF4 subsequently upregulates the proapoptotic gene CHOP and also modulates the transcription of a variety of genes in inflammation, oxidative stress, apoptosis, and stress responses.