ER stress and unfolded protein response in ocular health and disease

Abstract

The human eye is the organ that is able to react to light in order to provide sharp three-dimensional and colored images. Unfortunately, the health of the eye can be impacted by various stimuli that can lead to vision loss, such as environmental changes, genetic mutations, or aging. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling have been detected in many diverse ocular diseases, and chemical and genetic approaches to modulate ER stress and specific UPR regulatory molecules have shown beneficial effects in animal models of eye disease. This review highlights specific eye diseases associated with ER stress and UPR activity, based on a recent symposia exploring this theme.

Keywords: AMD; RGC; RPE; UPR; VEGF; ER stress; achromatopsia; glaucoma; neurodegernation; retinal degeneration.

Fig. 1.

Unfolded protein response signaling pathways. Schematic Illustration of the three unfolded protein response signaling pathways, comprised of inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Under unstressed conditions, the activity of these three UPR inducers is prevented by BiP binding. Ones ER stress occurs BiP dissociates and activates IRE1, PERK and ATF6. IRE1’s luminal domain is coupled to the cytosolic kinase (K) and endoribonuclease (R) domains. ER stress leads to IRE1 oligomerization, transautophosphorylation, and the unconventional splicing of X-box binding protein-1 (usXBP1) mRNA to generate spliced XBP1 (sXBP1). The PERK protein bears a luminal domain that is linked to a kinase domain. PERK activation causes its dimerization and phosphorylation of the eukaryotic translation initiation factor 2 subunit alpha (eIF2α), leading to attenuation of global protein translation. ATF6 migrates as a monomer from the ER to the Golgi compartment upon activation. Two independent proteases (S1P and S2P) cleave ATF6 to generate a potent transcription factor that contains a bZip domain to bind to DNA to upregulate its downstream targets.

Fig. 2.

Schematic representation of the human eye and retina. (A) Anatomy of the human eye with (B) detailing the structure and cell components of the human retina.

Fig. 3.

Classification of ATF6 mutations. Full length ATF6 can be present as a monomer, dimer, or oligomer using disulfide bond formations, once UPR signaling is activated BiP dissociates, and reduced monomeric ATF6 traffics from the ER to the Golgi compartment (see Fig. 1). Class 1 ATF6 mutations are trafficking mutations that show an impairment of translocation from the ER to the Golgi apparatus. Class 2 mutations of ATF6 present a fully intact cytosolic domain of ATF6 and show constitutive transcriptional activator function. Class 3 ATF6 mutations demonstrate a nonfunctional bZip domain and fail to bind and upregulate ATF6 specific targets.