Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded and recycled in RPE cells by two main machineries-the ubiquitin-proteasome system (UPS) and autophagy. Recent findings show that these systems can act together with a significant role of the EI24 (etoposide-induced protein 2.4 homolog) ubiquitin ligase in their action. On the other hand, E3 ligases are essential in both systems, but E3 is degraded by autophagy. The interplay between UPS and autophagy was targeted in several diseases, including Alzheimer disease. Therefore, cellular waste clearing in AMD should be considered in the context of such interplay rather than either of these systems singly. Aging and oxidative stress, two major AMD risk factors, reduce both UPS and autophagy. In conclusion, molecular mechanisms of UPS and autophagy can be considered as a target in AMD prevention and therapeutic perspective. Further work is needed to identify molecules and effects important for the coordination of action of these two cellular waste management systems.

Keywords: age-related macular degeneration; autophagy; cellular waste elimination; mitophagy; proteostasis; ubiquitin-proteasome system.

Figure 1

Schematic representation of the pathogenesis of age-related macular degeneration (AMD) with an important role of cellular waste (yellow highlight). Oxidative stress (red thunder) can be generated by many environmental/life style risk factors as well as yet unidentified sources. Visual cycle (VA) by-products can contribute to cellular waste. A complex interplay between oxidative stress, chronic inflammation, variants of genes encoding the complement and cellular waste clearing may lead to degeneration of retinal cells and clinically detectable AMD, which in its advanced stage may acquire the form of geographic atrophy (GA) or wet AMD, characterized by choroidal neovascularization (CNV). AMD symptoms include loss of central vision. Sharp black arrows indicate stimulation/consequences, whereas blunt black arrows—inhibition. PR—photoreceptors, RPE—retinal pigment epithelium, BM—Bruch’s membrane, Ch—choriocapillaris.

Figure 2

The visual cycle produces all-trans-retinal (atRAL), which is a major cellular waste in retinal cells. Light is absorbed by photoreceptors (PR) and causes isomerization of 11-cis-retinal to atRAL, which is transported and reduced to all-trans-retinol by ATP-binding transporter (ABCA4) and all trans retinal dehydrogenases RDH8/12, respectively. atRAL moves into retinal pigment epithelium (RPE), where it is converted to all-trans-retinyl esters by lecithin retinol acyltransferase (LRAT). RPE-specific protein (RPE65) isomerized these esters to 11-cis-retinol, which is then oxidized by RDH5 to 11-cis-retinal. Black arrows indicate a way from a compound to its derivative.

Figure 3

Fundus autofluorescence image from a degenerated macula indicating increased lipofuscin accumulation with increased autofluorescence signal.

Figure 4

Drusen are extracellular waste located between retinal pigment epithelium (RPE) cells and Bruch’s membrane (BM), which can disturb forward vision. They are clearly visible in fundus fluorescence as scattered light stains. PR—photoreceptors.

Figure 5

Cellular and extracellular waste clearing. Cellular waste, including misfolded, aggregated and damaged proteins as well as damaged organelles (presented as small ovals or squares of different colors) is subjected by two main machineries: ubiquitin-proteasome system (UPS) and autophagy, which can be in the form of macroautophagy, including mitophagy, microautophagy and chaperone-mediated autophagy (CMA). Unfolded proteins are a substrate for unfolded protein response (UPR, not represented here), which directs them to degradation either by autophagy or UPS. Heterophagy, which degrades extracellular debris inside the cell, is of a particular importance in retinal pigment epithelium cells and is usually carried out by endocytosis. Exosomes can transport waste material out of the cell. LAMP-2A—lysosomal associated membrane protein 2A. The black arrows indicate the sequence of events.

Figure 6

Unfolded protein response. When unfolded, misfolded and damaged proteins accumulate in endoplasmic reticulum (ER), they can induce unfolded protein response (UPR), a signaling cascade with the involvement of protein kinase-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). This cascade leads to a stop in translation of faulty proteins, degradation of misfolded proteins and increased synthesis of chaperons involved in protein folding. If these mechanisms fall, UPR switch to pro-apoptotic response. XBP1s—X-box binding protein 1 specificity protein, eIF2—translation initiation factor 2, ERAD—ER-associated degradation, ATF6f—the transcriptional activator domain of ATF6, P—phosphate residue.

Figure 7

EI24 (etoposide-induced protein 2.4 homolog) is the main connection between ubiquitin-mediated proteasomal system (UPS) and autophagy. The concerted action of ubiquitin ligases E1-E3 results in ubiquitination of target proteins to label for UPS-mediated degradation. Ubiquitin chain transfer to target proteins is catalyzed by the RING-domain E3 ligases. EI24, an autophagy-inducing protein, can cause autophagy-mediated degradation of RING-domain E3 ligases. Thick arrows represent main pathways, thin arrows—side pathways.