Lysosomes: Regulators of autophagy in the retinal pigmented epithelium

doi:10.1016/j.exer.2015.08.018

Experimental Eye Research

Volume 144, March 2016, Pages 46-53

https://doi.org/10.1016/j.exer.2015.08.018 Get rights and content

Highlights

•
In the RPE, lysosomes modulate both heterophagy and autophagy to maintain retinal homeostasis.
•
The mTORC1 signaling pathway regulates the biogenesis, distribution and activity of lysosomes.
•
βA3/A1-crystallin is a novel target for restoring normal lysosome function in human AMD disease.

Abstract

The retinal pigmented epithelium (RPE) is critically important to retinal homeostasis, in part due to its very active processes of phagocytosis and autophagy. Both of these processes depend upon the normal functioning of lysosomes, organelles which must fuse with (auto)phagosomes to deliver the hydrolases that effect degradation of cargo. It has become clear that signaling through mTOR complex 1 (mTORC1), is very important in the regulation of lysosomal function. This signaling pathway is becoming a target for therapeutic intervention in diseases, including age-related macular degeneration (AMD), where lysosomal function is defective. In addition, our laboratory has been studying animal models in which the gene (Cryba1) for βA3/A1-crystallin is deficient. These animals exhibit impaired lysosomal clearance in the RPE and pathological signs that are similar to some of those seen in AMD patients. The data demonstrate that βA3/A1-crystallin localizes to lysosomes in the RPE and that it is a binding partner of V-ATPase, the proton pump that acidifies the lysosomal lumen. This suggests that βA3/A1-crystallin may also be a potential target for therapeutic intervention in AMD. In this review, we focus on effector molecules that impact the lysosomal–autophagic pathway in RPE cells.

Section snippets

Retinal pigmented epithelium (RPE)

The RPE is a single layer of cells interposed between the neurosensory retina and Bruch's membrane (Strauss, 2005). En face, RPE cells assume a hexagonal, cobblestone-like appearance. The cells are highly polarized and contain abundant melanin granules that absorb scattered light, thereby reducing photo-oxidative stress on the retina (Beatty et al., 1999). In addition, the RPE has several other functions that are crucial to the retina's functional integrity. Perhaps its most important function

Lysosomes and autophagy

Much is now known about the molecular mechanisms of autophagosome formation (Mizushima and Komatsu, 2011, Yang and Klionsky, 2010, Rubinsztein et al., 2012), however, we know less about the end stages of macroautophagy, particularly the role of lysosomes in the degradation of autophagosome contents (Shen and Mizushima, 2014). The process is different from microautophagy and chaperone-mediated autophagy, where cellular materials to be degraded are directly delivered to the lysosomes, independent

mTOR signaling and autophagy

The mammalian target of rapamycin (mTOR), now officially known as the mechanistic TOR, is an atypical serine/threonine kinase that has been conserved throughout evolution. It interacts with many other proteins to form at least two distinct multiprotein complexes, namely mTORC1 and mTORC2 (Laplante and Sabatini, 2013). The mTOR complexes have different upstream inputs and downstream outputs (Zoncu et al., 2011). mTORC1 integrates multiple signals either to promote cellular growth when growth

Oxidative stress and autophagy

Postmitotic RPE cells in the macula are constantly exposed to a high metabolic and oxidative stress environment (Bok, 1993, Decanini et al., 2007). During RPE cell aging, the capacity to neutralize mitochondrial-derived ROS diminishes due to decreased anti-oxidant production, reduced ability to repair DNA or protein damage, and disturbed proteolysis (Kaarniranta et al., 2009, Blasiak et al., 2013). The inadequately neutralized ROS damage cellular proteins, leading to detrimental protein

Autophagy in retinal diseases

Autophagy clearly plays a protective role against disease in the retina and RPE. It has recently been found that the retina, and in particular the photoreceptors and RPE, of wild-type mice have constitutive autophagic events and that light exposure induces an autophagic response (Chen et al., 2013). Mice deficient in Beclin 1 or Atg7 develop severe retinal degeneration upon light exposure, indicating that autophagy is important for maintaining retinal homeostasis. Furthermore, impaired

Perspective

Lysosomes are a heterogeneous collection of distinct organelles, specialized for intracellular digestion. mTORC1 regulates the biogenesis, distribution, and activity of lysosomes. In neurodegenerative diseases, such as Alzheimer's and Parkinson's, several studies suggest that defective lysosomal clearance is involved in disease pathogenesis (Bergamini et al., 2004, Keller et al., 2004, Shintani and Klionsky, 2004). We believe that prolonged impairment of lysosomal clearance in the RPE, as seen

Acknowledgments

We would like to thank all members of Sinha, Kaarniranta, Handa and Lutty laboratories. DS is a recipient of the Carolyn K. McGillvray Memorial Award for Macular Degeneration Research from BrightFocus Foundation and the Sybil B. Harrington Special Scholar Award for Macular Degeneration from Research to Prevent Blindness. Dr. Handa is the Robert Bond Welch Professor. The authors would like to acknowledge funding support from National Institutes of Health: EY019037-S (DS), EY019904 (JTH) EY14005

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ReviewLysosomes: Regulators of autophagy in the retinal pigmented epithelium

Highlights

Abstract

Section snippets

Retinal pigmented epithelium (RPE)

Lysosomes and autophagy

mTOR signaling and autophagy

Oxidative stress and autophagy

Autophagy in retinal diseases

Perspective

Acknowledgments

Trends Cell Biol.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Trends Mol. Med.

J. Biol. Chem.

J. Biol. Chem.

Exp. Eye Res.

J. Biol. Chem.

Ageing Res. Rev.

Cell

J. Biol. Chem.

Ageing Res. Rev.

Exp. Eye Res.

Immunol. Lett.

Trends Cell Biol.

Int. J. Biochem. Cell Biol.

Cell

Exp. Eye Res.

Cell

Exp. Gerontol.

Cell

Curr. Biol.

Exp. Eye Res.

Cell

Trends Biochem. Sci.

Immunity

Mol. Cell. Neurosci.

Cell

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

Curr. Opin. Cell Biol.

Macular pigment and age related macular degeneration

Br. J. Ophthalmol.

Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration

FASEB J.

Where is mTOR and what is it doing there?

J. Cell Biol.

p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery

Autophagy

Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration

Int. J. Mol. Sci.

The retinal pigment epithelium: a versatile partner in vision

J. Cell Sci. Suppl.

Altered mTOR signaling in senescent retinal pigment epithelium

Invest. Ophthalmol. Vis. Sci.

p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy

Autophagy

Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration

Am. J. Ophthalmol.

Complement factor H polymorphism and age-related macular degeneration

Science

Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival

Nature

Autophagy and phagocytosis converge for better vision

Autophagy

The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium

Proc. Natl. Acad. Sci. U. S. A.

Complement factor H variant increases the risk of age-related macular degeneration

Science

The NALP3 inflammasome is involved in the innate immune response to amyloid-beta

Nat. Immunol.

Review
Lysosomes: Regulators of autophagy in the retinal pigmented epithelium