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Aleksander Tworak, Cheng-Kang Chiang, Brian M Kevany, Bo Xu, Janice Mayne, Zhibin Ning, Daniel Figeys, Krzysztof Palczewski; Profiling the regulatory networks controlling early steps of phagocytosis in the retinal pigmented epithelium. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3983.
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© ARVO (1962-2015); The Authors (2016-present)
Phagocytosis of photoreceptor outer segments (POS) by the retinal pigmented epithelium (RPE) plays a critical role in maintaining the viability of both rods and cones. The process undergoes circadian oscillations, exhibiting the highest intensity early each morning, shortly after light onset. Unfortunately, the detailed biochemical mechanisms that control phagocytosis in the RPE are not fully understood. Moreover, any dysfunction of these regulatory events can contribute to the pathogenesis of multiple retinal degenerative disorders including age-related macular degeneration, a leading cause of blindness in developed countries.
The human-derived RPE-like cell line ARPE-19, cultured murine primary RPE cells, and RPE samples from live mice were used to study global transcriptomic, proteomic, and phosphoproteomic changes resulting from the initiation of phagocytosis. Significant observations were confirmed with immunoblot analyses and in vitro phagocytosis assays. Computational methods were employed to identify possible interaction networks between proteins and phosphoproteins exhibiting significant responses to the induction of phagocytosis.
Our integrated analysis demonstrates that changes associated with the early stages of phagocytosis in the RPE are most pronounced at the level of protein phosphorylation. Global phosphoprotein enrichment analyses revealed involvement of multiple signaling pathways, including the PI3K/Akt, mTOR, and MEK/ERK phosphorylation cascades. Most striking, the phagocytosis of POS by cultured RPE cells was almost completely blocked by the inhibition of Akt phosphorylation.
Our data indicate that multiple phosphorylation cascades allow RPE cells to integrate different signals instigated by shed POS at various stages of the phagocytic process. In addition, our study provides a multi-level map of changes induced by phagocytosis that will guide additional efforts to identify regulatory mechanisms underlying photoreceptor phagocytosis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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