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ATP-Binding Cassette Transporter ABCA4 and Chemical Isomerization Protect Photoreceptor Cells from the Toxic Accumulation of Excess 11-Cis-Retinal

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ATP-Binding Cassette Transporter ABCA4 and Chemical Isomerization Protect Photoreceptor Cells from the Toxic Accumulation of Excess 11-Cis-Retinal ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal Faraz Quazi and Robert S. Molday1 Department of Biochemistry and Molecular Biology, Centre for Macular Research, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved February 25, 2014 (received for review January 15, 2014) The visual cycle is a series of enzyme-catalyzed reactions which disk membranes to facilitate the removal of all-trans-retinal from converts all-trans-retinal to 11-cis-retinal for the regeneration of disk membranes of rod and cone photoreceptor cells following visual pigments in rod and cone photoreceptor cells. Although photoexcitation. Recent studies have confirmed that ABCA4 can essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic flip the all-trans isomer of N-retinylidene-PE and PE from the due to its highly reactive aldehyde group and has to be detoxified lumen to the cytoplasmic leaflet of membranes (6, 10). However, by either reduction to retinol or sequestration within retinal-binding the light-dependent accumulation of lipofuscin and A2E in Abca4 proteins. Previous studies have focused on the role of the ATP-bind- knockout mice has been recently challenged. Boyer et al. (11) have ing cassette transporter ABCA4 associated with Stargardt macular shown that the levels and rates of increase in lipofuscin, including degeneration and retinol dehydrogenases (RDH) in the clearance trans the lipofuscin fluorophore A2E, were similar in dark-reared and of all- -retinal from photoreceptors following photoexcitation. Abca4 How rod and cone cells prevent the accumulation of 11-cis-retinal in cyclic light-reared knockout mice. These results and ex- cis photoreceptor disk membranes in excess of what is required for vi- periments showing that the addition of 11- -retinal to meta- sual pigment regeneration is not known. Here we show that ABCA4 bolically compromised photoreceptors results in the accumulation can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), of lipofuscin-like fluorophores have led to the suggestion that cis cis the Schiff-base conjugate of 11- -retinal and PE, from the lumen ABCA4 may play a more important role in the removal of 11- - NEUROSCIENCE to the cytoplasmic leaflet of disk membranes. This transport function retinal from photoreceptor outer segments although the mecha- together with chemical isomerization to its all-trans isomer and re- nism remains to be determined (11). ductiontoall-trans-retinol by RDH can prevent the accumulation of In this study we show that ABCA4 can transport the 11-cis excess 11-cis-retinal and its Schiff-base conjugate and the formation isomer of N-retinylidene-PE from the lumen to the cytoplasmic of toxic bisretinoid compounds as found in ABCA4-deficient mice and leaflet of membranes. This transport activity together with the individuals with Stargardt macular degeneration. This segment of the chemical isomerization of N-11-cis-retinylidene-PE to N-all-trans- cis- trans visual cycle in which excess 11- retinal is converted to all- - retinyldiene-PE and reduction of all-trans-retinal to all-trans-reti- retinol provides a rationale for the unusually high content of PE nol can remove excess 11-cis-retinal from disk membranes through and its long-chain unsaturated docosahexaenoyl group in photore- ceptor membranes and adds insight into the molecular mechanisms the visual cycle, thereby preventing the buildup of potentially toxic responsible for Stargardt macular degeneration. retinal and its bisretinoid condensation products. The high content of PE in disk membranes together with the long-chain docosa- ABC transporters | Stargardt disease | retinoids | photoreceptor hexaenoyl acid (DHA) group play crucial roles in the trapping of degeneration | retinal pigment epithelial cells 11-cis-retinal and enhancing the rate of chemical isomerization of N-11-cis-retinylidene-PE to its all-trans isomer. he visual cycle plays a crucial role in the removal of all-trans- Tretinal from photoreceptor cells following photoexcitation Significance and its conversion to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells (1). Deficient clear- ABCA4 is an ATP-binding cassette transporter encoded by the ance of all-trans-retinal and its Schiff-base conjugate N-retinylidene- gene responsible for Stargardt macular degeneration, an inheri- phosphatidylethanolamine (PE) from rod and cone photoreceptor ted retinopathy associated with severe vision loss. Previous outer segments results in condensation reactions which produce studies have shown that ABCA4 facilitates the clearance of all- a mixture of bisretinoid products including the pyridinium bisreti- trans-retinal from photoreceptor disc membranes following noid compound A2PE and its hydrolytic product A2E (2, 3). These photoexcitation. More recent studies implicate excess 11-cis-ret- bisretinoid compounds accumulate as lipofuscin deposits in retinal inal in the etiology of Stargardt disease. In this study we show N cis pigment epithelial (RPE) cells upon phagocytosis of outer segments the ABCA4 can transport the -11- -retinylidene-phosphatidyl- cis and have been implicated in the pathology of a number of retinal ethanolamine (PE), the Schiff-base adduct of 11- -retinal and PE, degenerative diseases. This is particularly evident in autosomal re- across membranes. This transport activity together with chemical isomerization of N-11-cis-retinylidene-PE to its all-trans isomer cessive Stargardt macular degeneration in which mutations in the and reduction to all-trans-retinol can prevent the accumulation of ATP-binding cassette (ABC) transporter ABCA4 which impair the cis N excess 11- -retinal and potentially toxic bisretinoid compounds -retinylidene-PE transport activity of ABCA4 cause a buildup of implicated in Stargardt and related retinal degenerative diseases. lipofuscin, atrophy of the central retina, and severe progressive loss – in vision (4 8). Author contributions: R.S.M. designed research; F.Q. performed research; F.Q. and R.S.M. In initial studies, Abca4 knockout mice were reported to show analyzed data; and F.Q. and R.S.M. wrote the paper. a light-dependent accumulation of all-trans-retinal, PE, and The authors declare no conflict of interest. N-retinylidene-PE in photoreceptors and lipofuscin and A2E in This article is a PNAS Direct Submission. RPE (9). This led to a model in which ABCA4 functions as a 1To whom correspondence should be addressed. E-mail: [email protected]. trans N lipid transporter flipping the all- isomer of -retinylidene- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. PE from the lumen to the cytoplasmic leaflet of photoreceptor 1073/pnas.1400780111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1400780111 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 Fig. 1. ATP-dependent retinoid transport activity from proteoliposomes reconstituted with ABCA4 to acceptor DOPE/DOPC vesicles. (A)[3H]-labeled 11-cis-retinal transfer with the addition (arrow) of 1 mM ATP (◇), AMP-PNP (□), or no addition (*); (B)[3H]-labeled all-trans-retinal with the addition of 1 mM ATP (▲), AMP- PNP (□), or no addition (*). (C) ATP-dependent retinal transfer activity as a function of 11-cis-retinal (o) and all-trans-retinal (▲). Solid line shows best-fit sigmoidal curve for 11-cis-retinal (K0.5 of 6.1 ± 0.4 μM and a Hill coefficient of 1.6 ± 0.3) and for all-trans-retinal (K0.5 of 6.9 ± 0.4 μM and a Hill coefficient of 1.7 ± 0.3). Data are the mean ± SD for three independent experiments. Results liposomes had a basal ATPase activity which was stimulated ABCA4 Transports both the 11-cis and all-trans Isomers of N- threefold by the 11-cis-retinal isomer and twofold by the all-trans retinylidene-PE. To explore the role of ABCA4 in the clearance isomer. Both isomers displayed Michaelis–Menten kinetics with K ∼ ± of 11-cis-retinal from photoreceptors, we first determined if similar apparent m values ( 0.23 0.02 mM) for ATP in the ABCA4 can transport the 11-cis isomer of N-retinylidene-PE presence of 40 μM retinal and showed a similar dependence of across membranes. This was measured using a biochemical assay ATPase activity on retinoid concentration (Fig. 2B). which quantifies the ATP-dependent transfer of radiolabeled We further investigated the possible role of 11-cis-retinal in 11-cis-retinal from donor dioleylphosphatidylethanolamine (DOPE)/ regulating the activity of ABCA4 because it had been reported dioleylphosphatidylcholine (DOPC) proteoliposomes reconstituted previously that 11-cis-retinal binds with high affinity to the bac- with ABCA4 to acceptor liposomes, a reaction driven by the terial expressed nucleotide-binding domain 1 (NBD1) of ABCA4 ATP-dependent transport or flipping of N-11-cis-retinylidene-PE (15). A modest increase in retinal-stimulated ATPase activity across the proteoliposome membrane by ABCA4 (6). The resulting was observed at higher (>20 μM) 11-cis-retinal concentrations in higher content of N-11-cis-retinylidene-PEontheouterleafletofthe the presence of 40 μM all-trans-retinal (Fig. 2C). This increase in proteoliposome, i.e., the side containing the ATP accessible nucle- activity, however, can be attributed to the enhanced ATPase otide-binding domains of ABCA4, together with dissociation into activation of ABCA4 by the 11-cis isomer together
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