ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation

Ptissam Bergam, Johannes M. Reisecker, Zsófia Rakvács, Nóra Kucsma, Graça Raposo, G. Szakács, Guillaume van Niel

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Genetically inheritable pigmentation defects provide a unique opportunity to reveal the function of proteins contributing to melanogenesis. Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis associated with mutations in the ABCB6 gene. Here we use optical and electron microscopy imaging combined with biochemical tools to investigate the localization and function of ABCB6 in pigment cells. We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1. Depletion of ABCB6 by siRNA impaired PMEL amyloidogenesis in early melanosomes and induced aberrant accumulation of multilamellar aggregates in pigmented melanosomes. PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation. In line with the impairment of PMEL matrix formation in the absence of ABCB6, morphological analysis of the retinal pigment epithelium of ABCB6 knockout mice revealed a significant decrease of melanosome numbers. Our study extends the localization of ABCB6 to melanosomes, suggesting a potential link between the function of ABCB6 and the etiology of DUH to amyloid formation in pigment cells.

Original languageEnglish
JournalJournal of Molecular Biology
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Melanosomes
Amyloid
Mutation
Retinal Pigment Epithelium
Pigmentation
Lysosomes
Knockout Mice
Small Interfering RNA
Electron Microscopy
Cell Line
Membranes
Genes
Dyschromatosis universalis hereditaria
Proteins

Keywords

  • ABC transporter
  • ABCB6
  • amyloid fibrils
  • pigmentation
  • PMEL

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation. / Bergam, Ptissam; Reisecker, Johannes M.; Rakvács, Zsófia; Kucsma, Nóra; Raposo, Graça; Szakács, G.; van Niel, Guillaume.

In: Journal of Molecular Biology, 01.01.2018.

Research output: Contribution to journalArticle

Bergam, Ptissam ; Reisecker, Johannes M. ; Rakvács, Zsófia ; Kucsma, Nóra ; Raposo, Graça ; Szakács, G. ; van Niel, Guillaume. / ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation. In: Journal of Molecular Biology. 2018.
@article{9c738709fe2144afbc937cd1c81f235a,
title = "ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation",
abstract = "Genetically inheritable pigmentation defects provide a unique opportunity to reveal the function of proteins contributing to melanogenesis. Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis associated with mutations in the ABCB6 gene. Here we use optical and electron microscopy imaging combined with biochemical tools to investigate the localization and function of ABCB6 in pigment cells. We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1. Depletion of ABCB6 by siRNA impaired PMEL amyloidogenesis in early melanosomes and induced aberrant accumulation of multilamellar aggregates in pigmented melanosomes. PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation. In line with the impairment of PMEL matrix formation in the absence of ABCB6, morphological analysis of the retinal pigment epithelium of ABCB6 knockout mice revealed a significant decrease of melanosome numbers. Our study extends the localization of ABCB6 to melanosomes, suggesting a potential link between the function of ABCB6 and the etiology of DUH to amyloid formation in pigment cells.",
keywords = "ABC transporter, ABCB6, amyloid fibrils, pigmentation, PMEL",
author = "Ptissam Bergam and Reisecker, {Johannes M.} and Zs{\'o}fia Rakv{\'a}cs and N{\'o}ra Kucsma and Gra{\cc}a Raposo and G. Szak{\'a}cs and {van Niel}, Guillaume",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jmb.2018.06.033",
language = "English",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation

AU - Bergam, Ptissam

AU - Reisecker, Johannes M.

AU - Rakvács, Zsófia

AU - Kucsma, Nóra

AU - Raposo, Graça

AU - Szakács, G.

AU - van Niel, Guillaume

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Genetically inheritable pigmentation defects provide a unique opportunity to reveal the function of proteins contributing to melanogenesis. Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis associated with mutations in the ABCB6 gene. Here we use optical and electron microscopy imaging combined with biochemical tools to investigate the localization and function of ABCB6 in pigment cells. We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1. Depletion of ABCB6 by siRNA impaired PMEL amyloidogenesis in early melanosomes and induced aberrant accumulation of multilamellar aggregates in pigmented melanosomes. PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation. In line with the impairment of PMEL matrix formation in the absence of ABCB6, morphological analysis of the retinal pigment epithelium of ABCB6 knockout mice revealed a significant decrease of melanosome numbers. Our study extends the localization of ABCB6 to melanosomes, suggesting a potential link between the function of ABCB6 and the etiology of DUH to amyloid formation in pigment cells.

AB - Genetically inheritable pigmentation defects provide a unique opportunity to reveal the function of proteins contributing to melanogenesis. Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis associated with mutations in the ABCB6 gene. Here we use optical and electron microscopy imaging combined with biochemical tools to investigate the localization and function of ABCB6 in pigment cells. We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1. Depletion of ABCB6 by siRNA impaired PMEL amyloidogenesis in early melanosomes and induced aberrant accumulation of multilamellar aggregates in pigmented melanosomes. PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation. In line with the impairment of PMEL matrix formation in the absence of ABCB6, morphological analysis of the retinal pigment epithelium of ABCB6 knockout mice revealed a significant decrease of melanosome numbers. Our study extends the localization of ABCB6 to melanosomes, suggesting a potential link between the function of ABCB6 and the etiology of DUH to amyloid formation in pigment cells.

KW - ABC transporter

KW - ABCB6

KW - amyloid fibrils

KW - pigmentation

KW - PMEL

UR - http://www.scopus.com/inward/record.url?scp=85049786514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049786514&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2018.06.033

DO - 10.1016/j.jmb.2018.06.033

M3 - Article

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

ER -