BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells

Rochin, Leila; Hurbain, Ilse; Serneels, Lutgarde; Fort, Cecile; Watt, Brenda; Leblanc, Pascal; Marks, Michael S.; De Strooper, Bart; Raposo, Graça; van Niel, Guillaume

doi:10.1073/pnas.1220748110

Cited by 202melanin and skin pigmentationMelanoma and MAPK PathwaysAlzheimer's disease research and treatments

BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells

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Rochin, Leila, Hurbain, Ilse, Serneels, Lutgarde, Fort, Cecile, Watt, Brenda, Leblanc, Pascal, Marks, Michael S., De Strooper, Bart +2 more·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1220748110PMC PMC3696817

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Abstract

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 causes depigmentation, the most consistent side effect in preclinical studies of BACE1/BACE2 inhibition.
“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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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;
ORCID: Hurbain, Ilse
Serneels, Lutgarde
Watt, Brenda
Leblanc, Pascal
Marks, Michael S.
Raposo, Graça
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
DOI: 10.1073/pnas.1220748110
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
Health Sciences › Medicine › Physiology › 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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BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells

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