Plasma membrane protein polarity and trafficking in RPE cells: Past, present and future

Abstract

The retinal pigment epithelium (RPE) comprises a monolayer of polarized pigmented epithelial cells that is strategically interposed between the neural retina and the fenestrated choroid capillaries. The RPE performs a variety of vectorial transport functions (water, ions, metabolites, nutrients and waste products) that regulate the composition of the subretinal space and support the functions of photoreceptors (PRs) and other cells in the neural retina. To this end, RPE cells display a polarized distribution of channels, transporters and receptors in their plasma membrane (PM) that is remarkably different from that found in conventional extra-ocular epithelia, e.g. intestine, kidney, and gall bladder. This characteristic PM protein polarity of RPE cells depends on the interplay of sorting signals in the RPE PM proteins and sorting mechanisms and biosynthetic/recycling trafficking routes in the RPE cell. Although considerable progress has been made in our understanding of the RPE trafficking machinery, most available data have been obtained from immortalized RPE cell lines that only partially maintain the RPE phenotype and by extrapolation of data obtained in the prototype Madin–Darby Canine Kidney (MDCK) cell line. The increasing availability of RPE cell cultures that more closely resemble the RPE in vivo together with the advent of advanced live imaging microscopy techniques provides a platform and an opportunity to rapidly expand our understanding of how polarized protein trafficking contributes to RPE PM polarity.

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

“…(3) Some vesicles are transported to CREs that are accessible to AP and BL recycling vesicles. Iron depleted Tf/TfR complex is recycled to the AP or BL plasma membrane domain from this pool by the slow recycling pathway [59, 73, 76]. (4) Tf binds ferric iron, and the Tf/TfR complex starts another cycle of endocytosis and recycling [78]).…”

“…This process releases significant amounts of iron which, unless exported, binds RPE cell melanin and can reach toxic concentrations. The BL membrane is separated from choroidal capillaries by the Bruch’s membrane, and regulates the transport of iron and other nutrients through specific transporters and receptors [50, 59]. Uptake of iron is mediated by the well-known Tf/TfR pathway, and export is accomplished by the iron export protein ferroportin (Fpn) coupled with the ferroxidase activity of ceruloplasmin (Cp) and hephaestin (Hp).…”

Molecular Principles for Decoding Homeostasis Disruptions in the Retinal Pigment Epithelium: Significance of Lipid Mediators to Retinal Degenerative Diseases

“…There is a marvelous interdependent relationship between PRC and RPE whereby key molecules are recycled (Bazan 2007;Lehmann et al 2014) by the daily shedding of PRC tips and RPE phagocytosis (Strauss 2005;Mukherjee et al 2007b;Mazzoni et al 2014). These include the tightly-regulated recycling of retinoids of the visual cycle in rod PRC.…”

Aberrant protein trafficking in retinal degenerations: The initial phase of retinal remodeling

“…The RPE provide a support system for the neural retina, offering retinoid recycling and processing, vectorial transport of metabolites and nutrients, receptor-mediated engulfment of shed OSs, provide a selective blood-retinal barrier and absorption of stray light (Young 1967, Lehmann, Benedicto et al 2014, Rizzolo 2014). One RPE cell supports up to 30–50 photoreceptors, providing diverse necessary support functions for the neural retina (Strauss 2005, Sparrow, Hicks et al.…”

“…One RPE cell supports up to 30–50 photoreceptors, providing diverse necessary support functions for the neural retina (Strauss 2005, Sparrow, Hicks et al. 2010, Lehmann, Benedicto et al 2014). To provide these support functions, the RPE have very long microvilli processes that surround rod photoreceptor outer segments (Figure 1) used for receptor-mediated phagocytosis of rod outer segment (ROS).…”