2. Academic Validation
  3. ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation

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

  • J Mol Biol. 2018 Oct 12;430(20):3802-3818. doi: 10.1016/j.jmb.2018.06.033.
Ptissam Bergam 1,  Johannes M Reisecker 2,  Zsófia Rakvács 3,  Nóra Kucsma 3,  Graça Raposo 1,  Gergely Szakacs 4,  Guillaume van Niel 5
Affiliations

Affiliations

  • 1 Institut Curie, PSL Research University, UMR144, Centre de Recherche, 26 rue d'Ulm, 75231 Paris, France; Centre National de la Recherche Scientifique, UMR144, Paris F-75248, France; Cell and Tissue Imaging Core Facility PICT-IBiSA, Institut Curie, Paris, France.
  • 2 Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
  • 3 Institute of Enzymology, Research Centre for National Sciences, HAS, Budapest 1117, Hungary.
  • 4 Institute of Cancer Research, Medical University Vienna, Vienna, Austria; Institute of Enzymology, Research Centre for National Sciences, HAS, Budapest 1117, Hungary. Electronic address: gergely.szakacs@meduniwien.ac.at.
  • 5 Institut Curie, PSL Research University, UMR144, Centre de Recherche, 26 rue d'Ulm, 75231 Paris, France; Centre National de la Recherche Scientifique, UMR144, Paris F-75248, France; Cell and Tissue Imaging Core Facility PICT-IBiSA, Institut Curie, Paris, France; Center for Psychiatry and Neuroscience, Hopital Saint-Anne, Université Descartes, INSERM U894, Paris, France. Electronic address: guillaume.van-niel@inserm.fr.
PMID: 29940187 DOI: 10.1016/j.jmb.2018.06.033
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; PMEL; amyloid fibrils; pigmentation.

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