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BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells
Open accessAbstract
Amyloids are often associated with pathologic processes such as in Alzheimer's disease (AD), but can also underlie physiological processes such as pigmentation. Formation of pathological and functional amyloidogenic substrates can require precursor processing by proteases, as exemplified by the generation of Aβ peptide from amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE)1 and γ-secretase. Proteolytic processing of the pigment cell-specific Melanocyte Protein (PMEL) is also required to form functional amyloid fibrils during melanogenesis, but the enzymes involved are incompletely characterized. Here we show that the BACE1 homologue BACE2 processes PMEL to generate functional amyloids. BACE2 is highly expressed in pigment cells and Bace2(-/-) but not Bace1(-/-) mice display coat color defects, implying a specific role for BACE2 during melanogenesis. By using biochemical and morphological analyses, combined with RNA silencing, pharmacologic inhibition, and BACE2 overexpression in a human melanocytic cell line, we show that BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. These studies identify an amyloidogenic substrate of BACE2, reveal an important physiological role for BACE2 in pigmentation, and highlight analogies in the generation of PMEL-derived functional amyloids and APP-derived pathological amyloids.
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“Pharmacological inhibition of BACE2 results in depigmentation, the most consistent side effect seen in preclinical studies of BACE1/BACE2 inhibition (9).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [9]
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Cites
Computer Visualization of Three-Dimensional Image Data Using IMOD
Kremer, J. R., Mastronarde, D. N., & McIntosh, J. R. (1996) · Journal of Structural Biology · doi:10.1006/jsbi.1996.0013 · Cited by 5,530
Protein detection using proximity-dependent DNA ligation assays
Fredriksson, S., Gullberg, M. T., Jarvius, J., Olsson, C., Pietras, K., Gustafsdottir, S., Östman, A., & Landegren, U. D. (2002) · Nature Biotechnology · doi:10.1038/nbt0502-473 · Cited by 1,518
Functional Amyloids As Natural Storage of Peptide Hormones in Pituitary Secretory Granules
Maji, S. K., Perrin, M. H., Sawaya, M. R., Jessberger, S., Vadodaria, K. C., Rissman, R. A., Singru, P. S., Nilsson, K. P. R., Simon, R. A., Schubert, D. A., et al. (2009) · Science · doi:10.1126/science.1173155 · Cited by 1,074
van Niel, G., Charrin, S., Simoes, S., Romao, M., Rochin, L., Saftig, P., Marks, M. S., Rubinstein, E., & Raposo, G. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.08.019 · Cited by 950
Functional Amyloid Formation within Mammalian Tissue
Fowler, D. M., Koulov, A. V., Alory, C., Marks, M. S., Balch, W. E., & Kelly, J. W. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0040006 · Cited by 847
The secretases: enzymes with therapeutic potential in Alzheimer disease
De Strooper, B., Vassar, R., & Golde, T. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.218 · Cited by 799
Melanosomes — dark organelles enlighten endosomal membrane transport
Raposo, G., & Marks, M. S. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2258 · Cited by 623
The Color Loci of Mice – A Genetic Century
Bennett, D. C., & Lamoreux, M. L. (2003) · Pigment Cell Research · doi:10.1034/j.1600-0749.2003.00067.x · Cited by 486
Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process
De Strooper, B. (2010) · Physiological Reviews · doi:10.1152/physrev.00023.2009 · Cited by 455
Raposo, G., Tenza, D., Murphy, D. M., Berson, J. F., & Marks, M. S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.4.809 · Cited by 451
Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice
Dominguez, D. I., Tournoy, J., Hartmann, D., Huth, T., Cryns, K., Deforce, S., Serneels, L., Espuny-Camacho, I., Marjaux, E., Craessaerts, K., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505249200 · Cited by 359
Pmel17 initiates premelanosome morphogenesis within multivesicular bodies
Berson, J. F., Harper, D. C., Tenza, D., Raposo, G., & Marks, M. S. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.11.3451 · Cited by 326
Berson, J. F., Theos, A. C., Harper, D. C., Tenza, D., Raposo, G., & Marks, M. S. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200302072 · Cited by 288
Critical Role of Amyloid-like Oligomers of Drosophila Orb2 in the Persistence of Memory
Majumdar, A., Cesario, W. C., White‐Grindley, E., Jiang, H., Ren, F., Khan, M. R., Li, L., Choi, E. M.-L., Kannan, K. S., Guo, F., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.004 · Cited by 275
Theos, A. C., Truschel, S. T., Tenza, D., Hurbain, I., Harper, D. C., Berson, J. F., Thomas, P. C., Raposo, G., & Marks, M. S. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.01.012 · Cited by 263
A model for melanosome biogenesis based on the purification and analysis of early melanosomes
Kushimoto, T., Basrur, V., Valencia, J. C., Matsunaga, J., Vieira, W. D., Ferrans, V. J., Müller, J., Appella, E., & Hearing, V. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.191184798 · Cited by 244
Rose, A. A. N., Annis, M. G., Dong, Z., Pepin, F., Hallett, M. T., Park, M., & Siegel, P. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012093 · Cited by 220
PMEL : a pigment cell‐specific model for functional amyloid formation
Watt, B., van Niel, G., Raposo, G., & Marks, M. S. (2013) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12067 · Cited by 195
SEIJI, M., FITZPATRICK, T. B., SIMPSON, R. T., & BIRBECK, M. S. C. (1963) · Nature · doi:10.1038/1971082a0 · Cited by 186
AP-1 and KIF13A coordinate endosomal sorting and positioning during melanosome biogenesis
Delevoye, C., Hurbain, I., Tenza, D., Sibarita, J., Uzan-Gafsou, S., Ohno, H., Geerts, W. J. C., Verkleij, A. J., Salamero, J., Marks, M. S., et al. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200907122 · Cited by 184
Dornier, E., Coumailleau, F., Ottavi, J., Moretti, J., Boucheix, C., Mauduit, P., Schweisguth, F., & Rubinstein, E. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201201133 · Cited by 175
Sun, X., He, G., & Song, W. (2006) · The FASEB Journal · doi:10.1096/fj.05-5632com · Cited by 163
Hurbain, I., Geerts, W. J. C., Boudier, T., Marco, S., Verkleij, A. J., Marks, M. S., & Raposo, G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803488105 · Cited by 160
Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation
Hellström, A. R., Watt, B., Fard, S. S., Tenza, D., Mannström, P., Narfström, K. L., Ekesten, B., Ito, S., Wakamatsu, K., Larsson, J., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002285 · Cited by 146
Bace2 Is a β Cell-Enriched Protease that Regulates Pancreatic β Cell Function and Mass
Esterházy, D., Stützer, I., Wang, H., Rechsteiner, M. P., Beauchamp, J., Döbeli, H., Hilpert, H., Matile, H., Prummer, M., Schmidt, A., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.018 · Cited by 135
BACE1 and BACE2 enzymatic activities in Alzheimer’s disease
Ahmed, R. R., Holler, C. J., Webb, R. L., Li, F., Beckett, T. L., & Murphy, M. P. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06528.x · Cited by 133
Dornier, E., Coumailleau, F., Ottavi, J., Moretti, J., Boucheix, C., Mauduit, P., Schweisguth, F., & Rubinstein, E. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.20120113304262016c · Cited by 133
Regulated Intramembrane Proteolysis of the Interleukin-1 Receptor II by α-, β-, and γ-Secretase
Kuhn, P.-H., Marjaux, E., Imhof, A., De Strooper, B., Haass, C., & Lichtenthaler, S. F. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700356200 · Cited by 120
N-terminal Domains Elicit Formation of Functional Pmel17 Amyloid Fibrils
Watt, B., van Niel, G., Fowler, D. M., Hurbain, I., Luk, K. C., Stayrook, S. E., Lemmon, M. A., Raposo, G., Shorter, J., Kelly, J. W., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.047449 · Cited by 115
Hoashi, T., Müller, J., Vieira, W. D., Rouzaud, F., Kikuchi, K., Tamaki, K., & Hearing, V. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601643200 · Cited by 104
Lopes, V. S., Wasmeier, C., Seabra, M. C., & Futter, C. E. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-03-0268 · Cited by 103
A non‐amyloidogenic function of BACE‐2 in the secretory pathway
Fluhrer, R., Capell, A., Westmeyer, G., Willem, M., Hartung, B., Condron, M. M., Teplow, D. B., Haass, C., & Walter, J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00908.x · Cited by 95
Theos, A. C., Berson, J. F., Theos, S. C., Herman, K. E., Harper, D. C., Tenza, D., Sviderskaya, E. V., Lamoreux, M. L., Bennett, D. C., Raposo, G., et al. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-01-0081 · Cited by 95
Stützer, I., Selevsek, N., Esterházy, D., Schmidt, A., Aebersold, R., & Stoffel, M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.444703 · Cited by 88
Harper, D. C., Theos, A. C., Herman, K. E., Tenza, D., Raposo, G., & Marks, M. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708007200 · Cited by 77
Identification of BACE2 as an avid ß-amyloid-degrading protease
Abdul‐Hay, S. O., Sahara, T., McBride, M., Kang, D., & Leissring, M. A. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-46 · Cited by 73
van Bebber, F., Hruscha, A., Willem, M., Schmid, B., & Haass, C. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12198 · Cited by 68
Kummer, M. P., Maruyama, H., Hülsmann, C., Baches, S., Weggen, S., & Koo, E. H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m808904200 · Cited by 60
Developmental Biology of Mammalian Melanocytes
Quevedo, W. C., & Fleischmann, R. D. (1980) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12521335 · Cited by 60
Proprotein Convertases Process Pmel17 during Secretion
Leonhardt, R. M., Vigneron, N., Rahner, C., & Cresswell, P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.168088 · Cited by 50
Dunn, L. C., & Thigpen, L. W. (1930) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a103275 · Cited by 47
Wang, J., Ohno‐Matsui, K., & Morita, I. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.05.085 · Cited by 46
Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production
Teranishi, Y., Hur, J., Gu, G. J., Kihara, T., Ishikawa, T., Nishimura, T., Winblad, B. G., Behbahani, H., Kamali‐Moghaddam, M., Frykman, S., et al. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.06.137 · Cited by 17
Research works printed but not linked: 1
- B Watt, G Raposo, MS Marks, Pmel17: An amyloid determinant of organelle structure. Functional Amyloid Aggregation, eds S Rigacci, M Bucciantini (Trivandrum, Kerala, India), pp. 89–113 (2010).
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Metadata
- Authors
- Rochin, L., Hurbain, I., Serneels, L., Fort, C., Watt, B., Leblanc, P., Marks, M. S., De Strooper, B., Raposo, G., & van Niel, G.
- Affiliations
- Institut Curie, Centre de Recherche and
- Centre National de la Recherche Scientifique (FR)
- KU Leuven (BE)
- University of Pennsylvania (US)
- École Normale Supérieure de Lyon (FR)
- Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, 3000 Leuven, Belgium;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-06-10
- Volume
- 110
- Issue
- 26
- Pages
- 10658-10663
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3696817
- OpenAlex
- W2074095545
- Cited by
- 186
- References
- 43
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 9 · 2023: 10 · 2022: 6 · 2021: 17 · 2020: 16 · 2019: 15 · 2018: 20 · 2017: 15 · 2016: 24 · 2015: 11 · 2014: 11 · 2013: 1
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-LABX-0038)
- National Institutes of Health (5r01ar048155-13)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR-048155)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- BACE2, PMEL, melanosomes, amyloid fibrils, melanogenesis, pigment cells, BACE1, amyloid precursor protein, pigmentation
- MeSH terms
- Amyloid, Animals, Cell Line, HeLa Cells, Humans, Melanins, Melanocytes, Mice, Inbred C57BL, Pigment Epithelium of Eye, Protein Processing, Post-Translational, RNA, Messenger, Skin Pigmentation, Aspartic Acid Endopeptidases, Mice, Knockout, Melanosomes, RNA, Small Interfering, Mice, Amyloid Precursor Protein Secretases, gp100 Melanoma Antigen
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