Defective phagosome motility and degradation in cell nonautonomous RPE pathogenesis of a dominant macular degeneration
Open accessAbstract
, suggesting photoreceptor cell loss in STGD3 occurs through two cell nonautonomous events: mutant photoreceptors first affect RPE cell pathogenesis, and then, second, RPE dysfunction leads to photoreceptor cell death. Here, we have investigated how the RPE pathology occurs, using a STGD3 mouse model in which mutant human ELOVL4 is expressed in the photoreceptors. We found that the mutant protein was aberrantly localized to the photoreceptor outer segment (POS), and that resulting POS phagosomes were degraded more slowly in the RPE. In cell culture, the mutant POSs are ingested by primary RPE cells normally, but the phagosomes are processed inefficiently, even by wild-type RPE. The mutant phagosomes excessively sequester RAB7A and dynein, and have impaired motility. We propose that the abnormal presence of ELOVL4 protein in POSs results in phagosomes that are defective in recruiting appropriate motor protein linkers, thus contributing to slower degradation because their altered motility results in slower basal migration and fewer productive encounters with endolysosomes. In the transgenic mouse retinas, the RPE accumulated abnormal-looking phagosomes and oxidative stress adducts; these pathological changes were followed by pathology in the neural retina. Our results indicate inefficient phagosome degradation as a key component of the first cell nonautonomous event underlying retinal degeneration due to mutant ELOVL4.
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The content of an OS phagosome influences its rate of degradation.
“A recent study has shown that the content of an OS phagosome influences its rate of degradation (Esteve-Rudd et al., 2018)”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Esteve-Rudd et al., 2018
These mice express mutant human ELOVL4 protein that mislocalizes to the OS, producing OS phagosomes with altered content which appear defective in their recruitment of motor linkers and motors, such as RAB7A and dynein.
“These mice express mutant human elongation of very long chain fatty acids (ELOVL)-4 protein that mislocalizes to the OS, producing OS phagosomes with altered content which, in turn, appear to be defective in their recruitment of motor linkers and motors, such as RAB7A and dynein (Esteve-Rudd et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Esteve-Rudd et al., 2018
Defective OS phagosome motility and degradation has been found in a mouse model of Stargardt macular degeneration (type 3), leading to phagosome accumulation, RPE pathogenesis, and photoreceptor cell death.
“In a second example, defective OS phagosome motility and degradation has been found in a mouse model of Stargardt macular degeneration (type 3) (Esteve-Rudd et al., 2018), leading to phagosome accumulation, RPE pathogenesis, and photoreceptor cell death (Karan et al., 2005).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Esteve-Rudd et al., 2018
OS phagosomes associate with subunits of both kinesin-1 and cytoplasmic dynein-1, which are plus- and minus-end directed microtubule motors, respectively, consistent with bidirectional motility along microtubules.
“Demonstrated association with subunits of both kinesin-1 (Jiang et al., 2015) and cytoplasmic dynein-1 (Esteve-Rudd et al., 2018), which are plus- and minus-end directed microtubule motors, respectively, is consistent with bidirectional motility along microtubules.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Esteve-Rudd et al., 2018
In a Stargardt macular degeneration type 3 mouse model, mutant ELOVL4 mislocalizes from the endoplasmic reticulum to the photoreceptor OSs; when these mutant OSs were fed to wild-type primary mouse RPE cells, the resulting OS phagosomes associated with excessive RAB7A, and had affected motor protein recruitment and impaired motility, which likely underlies their observed slower degradation.
“In a Stargardt macular degeneration type 3 mouse model, mutant ELOVL4 mislocalizes from the endoplasmic reticulum to the photoreceptor OSs. When these mutant OSs were fed to wild-type primary mouse RPE cells, the resulting OS phagosomes were found to associate with excessive RAB7A, and have affected motor protein recruitment and impaired motility, which likely underlies their observed slower”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Esteve-Rudd et al., 2018
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The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
Self-citationRapid differentiation of the human RPE cell line, ARPE-19, induced by nicotinamide
Hazim, R. A., Volland, S., Yen, A., Burgess, B. L., & Williams, D. S. (2019) · Experimental Eye Research · doi:10.1016/j.exer.2018.10.009 · Cited by 126 · see citing works
“The ARPE-19 cells differentiated by our method establish a polarized epithelial cell model that can be used to investigate general epithelial processes, including secretory and endocytic vesicular transport, as well as RPE-specific processes such as the trafficking of phagosomes and the degradative organelles that are…”
Background
- Authors
- Esteve-Rudd, J., Hazim, R. A., Diemer, T., Paniagua, A. E., Volland, S., Umapathy, A., & Williams, D. S.
- Affiliations
- Department of Ophthalmology and Stein Eye Institute, University of California, Los Angeles (UCLA), Los Angeles, CA 90095;
- University of California, Los Angeles (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-05-07
- Volume
- 115
- Issue
- 21
- Pages
- 5468-5473
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6003516
- OpenAlex
- W2803510612
- Cited by
- 42
- References
- 38
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 3 · 2018: 2
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Eye Institute (F31EY026805, R01EY013408, R01EY027442, and P30EY000331)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- ELOVL4, retinal pigment epithelium, photoreceptor outer segments, Rab7, dynein, oxidative stress, macular degeneration, photoreceptor cell death, transgenic mouse model
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Disease Models, Animal, Eye Proteins, Genes, Dominant, Humans, Macular Degeneration, Membrane Proteins, Mice, Transgenic, Mutation, Phagosomes, Photoreceptor Cells, Mice, Retinal Pigment Epithelium
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