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Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium

Published online by Cambridge University Press:  23 April 2013

LAURA S. FROST ,
VANDA S. LOPES ,
FRANK P. STEFANO ,
ALVINA BRAGIN ,
DAVID S. WILLIAMS ,
CLAIRE H. MITCHELL  and
KATHLEEN BOESZE-BATTAGLIA
LAURA S. FROST
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
VANDA S. LOPES
Affiliation:
Departments of Ophthalmology and Neurobiology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California
FRANK P. STEFANO
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
ALVINA BRAGIN
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
DAVID S. WILLIAMS
Affiliation:
Departments of Ophthalmology and Neurobiology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California
CLAIRE H. MITCHELL
Affiliation:
Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
KATHLEEN BOESZE-BATTAGLIA*
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
*
Address correspondence to: Kathleen Boesze-Battaglia, Department of Biochemistry, University of Pennsylvania, Philadelphia, PA 19104. E-mail: battagli@upenn.edu
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Abstract

Cathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.

Keywords

Retinal pigment epitheliumCathepsin-D processingPhagocytosisProtease secretion
Type
Research Articles
Information
Visual Neuroscience , Volume 30 , Issue 3 , May 2013 , pp. 55 - 64
Copyright
Copyright © Cambridge University Press 2013 

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References

Ahmado, A., Carr, A.J., Vugler, A.A., Semo, M., Gias, C., Lawrence, J.M., Chen, L.L., Chen, F.K., Turowski, P., da Cruz, L. & Coffey, P.J. (2011) Induction of differentiation by pyruvate and DMEM in the human retinal pigment epithelium cell line ARPE-19. Investigative Ophthalmology and Visual Science 52, 7148–7159.CrossRefGoogle ScholarPubMed
Azarian, S., McLeod, I., Lillo, C., Gibbs, D., Yates, J.R. & Williams, D.S. (2006). Proteomic analysis of mature melanosomes from the retinal pigment epithelium. Journal of Proteomic Research 5, 521–529.CrossRefGoogle Scholar
Bazan, N.G., Calandria, J.M. & Serhan, C.N. (2010). Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. Journal of Lipid Research 51, 2018–2031.CrossRefGoogle ScholarPubMed
Benes, P., Vetvicka, V. & Fusek, M. (2008). Cathepsin D: Many functions of one aspartic protease. Critical Reviews in Oncology/Hematology 68, 12–28.CrossRefGoogle ScholarPubMed
Besharse, J.C., DeFoe, D.M., Marmor, M.F. & Wolfensberger, T.J. (1998). Role of the retinal pigment epithelium in photoreceptor membrane turnover. In The Retinal Pigment Epithelium, ed. Besharse, J.C., Vol. 8, p. 152. New York: Oxford University Press.Google Scholar
Blott, E.J. & Griffiths, G.M. (2002). Secretory lysosomes. Nature 3, 122–131.Google ScholarPubMed
Boesze-Battaglia, K., Song, H., Sokolov, M., Lillo, C., Pankoski-Walker, L., Gretzula, C., Gallagher, B., Rachel, R.A., Jenkins, N.A., Copeland, N.G., Morris, F., Jacob, J., Yeagle, P., Williams, D.S. & Damek-Poprawa, M. (2007). The tetraspanin protein peripherin-2 forms a complex with melanoregulin, a putative membrane fusion regulator. Biochemistry 46, 1256–1272.CrossRefGoogle ScholarPubMed
Bosch, E., Horwitz, J. & Bok, D. (1993). Phagocytosis of outer segments by retinal pigment epithelium: Phagosome-lysosome interaction. The Journal of Histochemistry and Cytochemistry 41, 253.CrossRefGoogle ScholarPubMed
Cai, J., Nelson, K.C., Wu, M., Sternberg, P., Jr. & Jones, D.P. (2000). Oxidative damage and protection of the RPE. Progress in Retinal and Eye Research 19, 205–221.CrossRefGoogle ScholarPubMed
Capony, F., Braulke, T., Rougeot, C., Roux, S., Montcourrier, P. & Rochefort, H. (1994). Specific mannose-6-phosphate receptor-independent sorting of pro-cathepsin D in breast cancer cells. Experimental Cell Research 215, 154–163.CrossRefGoogle ScholarPubMed
Capurso, C., Solfrizzi, V., D’Introno, A., Colacicco, A.M., Capurso, S.A., Bifaro, L., Menga, R., Santamato, A., Seripa, D., Pilotto, A., Capurso, A. & Panza, F. (2008). Short arm of chromosome 11 and sporadic Alzheimer’s disease: Catalase and cathepsin D gene polymorphisms. Neuroscience Letters 432, 237–242.CrossRefGoogle ScholarPubMed
Damek-Poprawa, M., Diemer, T., Lopes, V.S., Lillo, C., Harper, D.C., Marks, M.S., Wu, Y., Sparrow, J.R., Rachel, R.A., Williams, D.S. & Boesze-Battaglia, K. (2009). Melanoregulin (MREG) modulates lysosome function in pigment epithelial cells. The Journal of Biological Chemistry 284, 10877–10889.CrossRefGoogle ScholarPubMed
Deguchi, J., Yamamoto, A., Yoshimori, T., Sugasawa, K., Moriyama, Y., Futai, M., Suzuki, T., Kato, K., Uyama, M. & Tashiro, Y. (1994). Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium. Investigative Ophthalmology and Visual Science 35, 568–579.Google ScholarPubMed
Delbruck, R., Desel, C., von Figura, K. & Hille-Rehfeld, A. (1994). Proteolytic processing of cathepsin D in prelysosomal organelles. European Journal of Cell Biology 64, 7–14.Google ScholarPubMed
Delcourt, C., Cristol, J.P., Leger, C.L., Descomps, B. & Papoz, L. (1999). Associations of antioxidant enzymes with cataract and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liées à l’Age. Ophthalmology 106, 215–222.CrossRefGoogle ScholarPubMed
Dunn, K.C., Aotaki-Keen, A.E., Putkey, F.R. & Hjelmel, L.M. (1996). ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Experimental Eye Research 62, 155–169.CrossRefGoogle ScholarPubMed
Erdmann, S., Ricken, A., Hummitzsch, K., Merkwitz, C., Schliebe, N., Gaunitz, F., Strotmann, R. & Spanel-Borowski, K. (2008). Inflammatory cytokines increase extracellular procathepsin D in permanent and primary endothelial cell cultures. European Journal of Cell Biology 87, 311–323.CrossRefGoogle ScholarPubMed
Fusek, M. & Vetvicka, V. (2005). Dual role of cathepsin D: Ligand and protease. Biomedical papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia 149, 43–50.CrossRefGoogle ScholarPubMed
Garcia, M., Platet, N., Liaudet, E., Laurent, V., Derocq, D., Brouillet, J.P. & Rochefort, H. (1996). Biological and clinical significance of cathepsin D in breast cancer metastasis. Stem Cells 14, 642–650.CrossRefGoogle ScholarPubMed
Gee, K., Angel, J.B., Ma, W., Mishra, S., Gajanayaka, N., Parato, K. & Kumar, A. (2006). Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. The Journal of Biological Chemistry 281, 31647–31658.Google ScholarPubMed
Gibbs, D., Kitamoto, J. & Williams, D.S. (2003). Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proceedings of the National Academy of Sciences of the United States of America 100, 6481–6486.CrossRefGoogle Scholar
Haque, A., Banik, N.L. & Ray, S.K. (2008). New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer’s disease: Cathepsin inhibitors as potential therapeutics. CNS & Neurological Disorders Drug Targets 7, 270–277.CrossRefGoogle ScholarPubMed
Hasilik, A. & Neufeld, E.F. (1980). Biosynthesis of lysosomal enzymes in fibroblasts. Synthesis as precursors of higher molecular weight. The Journal of Biological Chemistry 255, 4937–4945.CrossRefGoogle ScholarPubMed
Hayasaka, S. & Hsa, M.K. (1975). Degradation of rod outer segment proteins by cathepsin D. The Journal of Biological Chemistry 78, 1365–1367.Google ScholarPubMed
Hoppe, G., Marmorstein, A.D., Pennock, E.A. & Hoff, H.F. (2001). Oxidized low density lipoprotein-induced inhibition of processing of photoreceptor outer segments by RPE. Investigative Ophthalmology and Visual Science 42, 2714–2720.Google ScholarPubMed
Hoppe, G., O’Neil, J., Hoff, H.F. & Sears, J. (2004 a). Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium. Cellular and Molecular Life Sciences: CMLS 61, 1664–1674.CrossRefGoogle ScholarPubMed
Hoppe, G., O’Neil, J., Hoff, H.F. & Sears, J. (2004 b). Products of lipid peroxidation induce missorting of the principal lysosomal protease in retinal pigment epithelium. Biochim Biophys Acta 1689, 33–41.CrossRefGoogle ScholarPubMed
Hu, L., Roth, J.M., Brooks, P., Luty, J. & Karpatkin, S. (2008). Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Research 68, 4666–4673.CrossRefGoogle ScholarPubMed
Kanda, A., Abecasis, G. & Swaroop, A. (2008). Inflammation in the pathogenesis of age-related macular degeneration. The British Journal of Ophthalmology 92, 448–450.CrossRefGoogle ScholarPubMed
Kevany, B.M. & Palczewski, K. (2010). Phagocytosis of retinal rod and cone photoreceptors. Physiology 25, 8–15.CrossRefGoogle ScholarPubMed
Khalkhali-Ellis, Z., Abbott, D.E., Bailey, C.M., Goossens, W., Margaryan, N.V., Gluck, S.L., Reuveni, M. & Hendrix, M.J. (2008). IFN-gamma regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells. Journal of Cellular Biochemistry 105, 208–218.CrossRefGoogle ScholarPubMed
Koike, M., Shibata, M., Ohsawa, Y., Nakanishi, H., Koga, T., Kametaka, S., Waguri, S., Momoi, T., Kominami, E., Peters, C., Figura, K., Saftig, P. & Uchiyama, Y. (2003). Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice. Molecular and Cellular Neurosciences 22, 146–161.CrossRefGoogle ScholarPubMed
Kokkonen, N., Rivinoja, A., Kauppila, A., Suokas, M., Kellokumpu, I. & Kellokumpu, S. (2004). Defective acidification of intracellular organelles results in aberrant secretion of cathepsin D in cancer cells. The Journal of Biological Chemistry 279, 39982–39988.CrossRefGoogle ScholarPubMed
Kon, M. & Cuervo, A.M. (2010). Chaperone-mediated autophagy in health and disease. FEBS Letters 584, 1399–1404.CrossRefGoogle ScholarPubMed
Kornfeld, S. (1990). Lysosomal enzyme targeting. Biochemical Society Transactions 18, 367–374.CrossRefGoogle ScholarPubMed
LaVail, M.M. (1978). The retinal pigment epithelium in mice and rats with inherited retinal degeneration. In The Retinal Pigment Epitheilium, Vol. 20, pp. 357.Google Scholar
LaVail, M.M. (1980). Circadian nature of rod outer segment disc shedding in the rat. Investigative Ophthalmology and Visual Science 19, 407.Google ScholarPubMed
Li, C.M.Chung, B.H.Presley, J.B.Malek, G.Zhang, X.Dashti, N.Li, L.Chen, J.Bradley, K., Kruth, H.S.Curcio, C.A. (2005). Lipoprotein-like particles and cholesteryl esters in human Bruch’s membrane: Initial characterization. Investigative Ophthalmology and Visual Science 46, 2576–2586.CrossRefGoogle ScholarPubMed
Malek, G., Li, C.M.Guidry, C.Medeiros, N.E.Curcio, C.A. (2003). Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. The American Journal of Pathology 162, 413–425.CrossRefGoogle ScholarPubMed
McKechnie, N.M., King, B.C., Fletcher, E.Braun, G. (2006). Fas-ligand is stored in secretory lysosomes of ocular barrier epithelia and released with microvesicles. Experimental Eye Research 83, 304–314.CrossRefGoogle ScholarPubMed
O’Sullivan, T.N., Wu, X.S.Rachel, R.A.Huang, J.D.Swing, D.A.Matesic, L.E.Hammer, J.A.3rd Copeland, N.G.Jenkins, N.A. (2004). dsu functions in a MYO5A-independent pathway to suppress the coat color of dilute mice. Proceedings of the National Academy of Sciences of the United States of America 101, 16831–16836.CrossRefGoogle Scholar
Ohbayashi, N., Maruta, Y.Ishida, M.Fukuda, M. (2012). Melanoregulin regulates retrograde melanosome transport through interaction with the RILP·p150Glued complex in melanocytes. Journal of Cell Science.CrossRefGoogle ScholarPubMed
Rachel, R.A., Nagashima, K.O’Sullivan, T.N.Frost, L.S.Stefano, F.P.Marigo, V.Boesze-Battaglia, K. (2012). Melanoregulin, product of the dsu locus, links the BLOC-pathway and Oa1 in organelle biogenesis. PLoS One 7, e42446.CrossRefGoogle ScholarPubMed
Rakoczy, P.E., Baines, M.Kennedy, C.J.Constable, I.J. (1996 a). Correlation between autofluorescent debris accumulation and the presence of partially processed forms of cathepsin D in cultured retinal pigment epithelial cells challenged with rod outer segments Experimental Eye Research 63, 159–167.CrossRefGoogle ScholarPubMed
Rakoczy, P.E., Lai, M.C.Vijayasekaran, S.Robertson, T.Rapp, L.Papadimitriou, J.Constable, I. (1996 b). Initiation of impaired outer segment degradation in vivo using an antisense oligonucleotide. Current Eye Research 15, 119–123.CrossRefGoogle ScholarPubMed
Rakoczy, P.E., Lai, M.C.Watson, M.Seydel, U.Constable, I. (1996 c). Targeted delivery of an antisense oligonucleotide in the retina: Uptake, distribution, stability, and effect. Antisense & Nucleic Acid Drug Development, 6, 207–213.CrossRefGoogle ScholarPubMed
Rakoczy, P.E., Lai, C.M.Baines, M.Di Grandi, S.Fitton, J.H.Constable, I.J. (1997). Modulation of cathepsin D activity in retinal pigment epithelial cells. Journal of Biochemistry 324, 935–940.CrossRefGoogle ScholarPubMed
Rakoczy, P.E., Zhang, D.Robertson, T.Barnett, N.L.Papadimitriou, J.Constable, I.J.Lai, C.M. (2002). Progressive age-related changes similar to age-related maculardegeneration in a transgenic mouse model. The American Journal of Pathology 161, 1515–1524.CrossRefGoogle Scholar
Saftig, P., Hetman, M.Schmahl, W.Weber, K.Heine, L.Mossmann, H.Koster, A.Hess, B.Evers, M.von Figura, K. (1995). Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. The EMBO Journal 14, 3599–3608.CrossRefGoogle ScholarPubMed
Siintola, E., Partanen, S.Stromme, P.Haapanen, A.Haltia, M.Maehlen, J.Lehesjoki, A.E.Tyynela, J. (2006). Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129, 1438–1445.CrossRefGoogle ScholarPubMed
Steinfeld, R., Reinhardt, K.Schreiber, K.Hillebrand, M.Kraetzner, R.Bruck, W.Saftig, P.Gartner, J. (2006). Cathepsin D deficiency is associated with a human neurodegenerative disorder. American Journal of Human Genetics 78, 988–998.CrossRefGoogle ScholarPubMed
Stewart, S.A.A., Dykxhoorn, D.M.Palliser, D.Mizuno, H.Yu, E.Y.An, D.S.Sabatini, D.M.Chen, I.S.Y.Hahn, W.C.Sharp, P.A.Weinberg, R.A.Novina, C.D. (2003). Lentivirus-delivered stable gene silencing by RNA in primary cells RNA 9, 493–501.CrossRefGoogle ScholarPubMed
Tikellis, G., Robman, L.D.Dimitrov, P.Nicolas, C.McCarty, C.A.Guymer, R.H. (2007). Characteristics of progression of early age-related macular degeneration: The cardiovascular health and age-related maculopathy study. Eye 21, 169–176.CrossRefGoogle ScholarPubMed
Urbanelli, L., Emiliani, C.Massini, C.Persichetti, E.Orlacchio, A.Pelicci, G.Sorbi, S.Hasilik, A.Bernardi, G.Orlacchio, A. (2008). Cathepsin D expression is decreased in Alzheimer’s disease fibroblasts. Neurobiology of Aging 29, 12–22.CrossRefGoogle ScholarPubMed
Vetvicka, V., Vektvickova, J.Fusek, M. (1994). Effect of human procathepsin D on proliferation of human cell lines. Cancer Letters 79, 131–135.CrossRefGoogle ScholarPubMed
Vetvicka, V. & Vetvickova, J. (2011). Procathepsin D and cytokines influence the proliferation of lung cancer cells. Anticancer Research 1, 47–51.Google Scholar
Woessner, J.F. Jr. (1977). Specificity and biological role of cathepsin D. Advances in Experimental Medicine and Biology 95, 313–327.CrossRefGoogle ScholarPubMed
Zaidi, N., Maurer, A.Nieke, S.Kalbacher, H. (2008). Cathepsin D: A cellular roadmap. Biochemical and Biophysical Research Communications 376, 5–9.CrossRefGoogle ScholarPubMed
Zarbin, M.A. (2004). Current concepts in the pathogenesis of age-related macular degeneration. Archives of Ophthalmology 122, 598–614.CrossRefGoogle ScholarPubMed
Zareparsi, S., Buraczynska, M.Branham, K.E.Shah, S.Eng, D.Li, M.Pawar, H.Yashar, B.M.Moroi, S.E.Lichter, P.R.Petty, H.R.Richards, J.E.Abecasis, G.R.Elner, V.M.Swaroop, A. (2005). Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Human Molecular Genetics 14, 1449–1455.CrossRefGoogle ScholarPubMed
Zufferey, R. (1997). Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nature Biotechnology 15, 871–885.CrossRefGoogle ScholarPubMed