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Melanosomes — dark organelles enlighten endosomal membrane transport

Key Points

  • Melanosomes are specialized intracellular organelles of pigment cells in which melanin pigments are synthesized and stored. They are members of a family of cell-type-specific lysosome-related organelles (LROs) that coexist with traditional endosomes and lysosomes and are generated from them through a progressive series of membrane sorting steps.

  • Early stage melanosomes harbour intralumenal fibrils that have characteristics of pathogenic amyloid fibrils, and that serve in later stages to concentrate and detoxify melanin intermediates. Like many pathogenic amyloids, the fibrils predominantly consist of proteolytic fragments of a single protein, in this case the pigment-cell-specific protein PMEL17. PMEL17 fibrils begin to form on intralumenal membranes of multivesicular early endosomes. Active sorting to these intralumenal membranes is required for fibril formation and is mediated by a ubiquitin-independent and endosomal sorting complexes required for transport (ESCRT)-independent mechanism that requires a lumenal determinant. PMEL17 is similarly sorted even when it is ectopically expressed in non-melanocytic cells, which indicates that the mechanism is not limited to specialized cell types.

  • Constituents of late stage, pigmented melanosomes are separately sorted from the constituents of early stage melanosomes and late endosomes or lysosomes within early endosomes. This process is disrupted in Hermansky–Pudlak syndrome (HPS), a group of genetic diseases that affect the formation of melanosomes and several other LROs by disabling one of several ubiquitous protein complexes that are involved in protein delivery to LROs.

  • Biochemical analyses of the proteins encoded by genes that are disrupted in HPS, coupled with analyses of melanosome cargo trafficking in melanocytes from human and murine HPS models, have revealed that the AP-3 clathrin adaptor complex and the biogenesis of LRO complex-1 (BLOC-1) and BLOC-2 regulate at least two cargo trafficking pathways from early endosomes to melanosomes. AP-3 and BLOC-1 regulate cargo exit from distinct early endosomal membrane domains, whereas BLOC-2 operates downstream of BLOC-1 and regulates cargo delivery to melanosomes.

  • Genetic analyses indicate that specialized members of the Rab family of GTPases, including the tissue-specific RAB32 and RAB38, cooperate with AP-3 and BLOCs to regulate the delivery of melanosome-bound cargo proteins. Cargo transport is also regulated by ubiquitous endosomal SNAREs (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptors), some of which interact with BLOCs and AP-3 and show increased expression in melanocytes relative to other cell types, and by SNARE-associated Sec1/Munc18 family members.

  • Pigment-cell-specific transmembrane ion transporters, a melanosome-associated G-protein coupled receptor and the γ-secretase-associated presenilins are required for proper melanosome biogenesis, and mutations in these proteins alter trafficking between endosomes and melanosomes. These proteins probably reflect generalized requirements for similar proteins in regulating the formation of most conventional and specialized endosomal organelles.

Abstract

Melanosomes are tissue-specific lysosome-related organelles of pigment cells in which melanins are synthesized and stored. Analyses of the trafficking and fate of melanosomal components are beginning to reveal how melanosomes are formed through novel pathways from early endosomal intermediates. These studies unveil generalized structural and functional modifications of the endosomal system in specialized cells, and provide unexpected insights into the biogenesis of multivesicular bodies and how compartmentalization regulates protein refolding. Moreover, genetic disorders that affect the biogenesis of melanosomes and other lysosome-related organelles have shed light onto the molecular machinery that controls specialized endosomal sorting events.

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Figure 1: Ultrastructural characterization of melanosomes.
Figure 2: Model for the formation of premelanosome fibrils.
Figure 3: Endosomal protein complexes that regulate cargo sorting to melanosomes.
Figure 4: Model of melanosome maturation.

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Acknowledgements

We thank all members of our laboratories for their contributions to many of the studies described here, including Figure 1 (I. Hurbain) and Figure 3 (D. Tenza). We also thank E. Dell'Angelica, J. Bonifacino, E. Coudrier, W. Stoorvogel, D. Cutler, D. Rimoldi, M. V. Schiaffino and M. Seabra for valuable discussions. We apologise to those authors whom we did not cite due to space limitations. This work was funded by grants from the National Institutes of Health (to M.S.M. and G.R.), Institut Curie, CNRS, Fondation pour la Recherche Médicale, Institut National du Cancer and Cancéropole Ile de France (to G.R.).

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DATABASES

OMIM

Alzheimer's disease

familial amyloidosis of Finnish type

Griscelli syndrome

Hermansky–Pudlak syndrome

ocular albinism type I

Parkinson's disease

polycystic kidney disease

spongiform encephalopathies

FURTHER INFORMATION

Michael S. Marks's homepage

Graça Raposo's homepage

Glossary

Lysosome-related organelle

(LRO). One of a class of tissue-specific intracellular organelles that share some features with lysosomes, such as acidic pH and lysosomal membrane protein and enzyme content.

Eumelanins

The polymerized and cyclized products of successive oxidation reactions for which Tyr is the initial substrate.

Pheomelanins

The polymerized products of glutathionyl or cysteinyl adducts of Tyr and its oxidation product, L-3,4-dihydroxyphenylalanine (DOPA) quinone.

Dynein

A motor protein complex that regulates motility along microtubules, predominantly towards the minus end (toward the microtubule-organizing centre).

Kinesin

One of a family of motor proteins that regulate microtubule-based motility, predominantly towards the plus end (away from the microtubule-organizing centre).

Proprotein convertase

One of a small family of related proteinases that release mature peptides from many inactive proprotein precursors, including prohormones such as proinsulin.

Weibel–Palade body

An LRO found in endothelial cells that is characterized by tubular fibrils of proteolytically processed von Willebrand factor.

Amyloid

Fibrous structures that are composed of polymers of typically a single protein in a specific cross-β-sheet pattern. Amyloid structures are associated with pathology in neurodegenerative diseases.

Clathrin

A coat protein that forms patches on the plasma membrane, endosomes or the TGN and is typically involved in budding of vesicles. Clathrin also has structural roles in defining endosomal membrane domains.

Multivesicular body

(MVB). An endosomal domain that contains internal vesicles that are formed by invagination of the limiting membrane. Most mature MVBs correspond to late endosomes.

Ubiquitylation

The process by which the conserved 76-residue polypeptide, ubiquitin, is covalently conjugated to substrates.

Ubiquitin ligase

Also known as E3 enzyme. This enzyme binds to substrate proteins and is required directly or indirectly for conjugation to ubiquitin.

Rab GTPase

A member of the largest subfamily within the superfamily of Ras small GTPases, each with its own function in membrane budding, fusion or motility.

SNARE

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor. These are membrane-associated proteins that are required for target membrane recognition and membrane fusion in the secretory and endocytic pathways.

Symporter

An ion transporter that moves more than one type of ion across the same membrane at the same time.

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Raposo, G., Marks, M. Melanosomes — dark organelles enlighten endosomal membrane transport. Nat Rev Mol Cell Biol 8, 786–797 (2007). https://doi.org/10.1038/nrm2258

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