Melanocytes Derived from Patients with Hermansky–Pudlak Syndrome Types 1, 2, and 3 Have Distinct Defects in Cargo Trafficking

Richmond, Bonnie L.; Huizing, Marjan; Knapp, Jill; Koshoffer, Amy; Zhao, Yang; Gahl, William A.; Boissy, Raymond E.

doi:10.1111/j.0022-202x.2004.23585.x

Cited by 54 publications

(66 citation statements)

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“…The HPS-associated protein complex BLOC-2 seems to function downstream of BLOC-1 in this pathway, but AP-3 seems to regulate different cargo. Our data have important implications Previous evidence has demonstrated selective endosomal protein sorting defects in AP-3-deficient melanocytes (Huizing et al, 2001;Theos et al, 2005), altered distribution of selected melanosomal cargo in BLOC-3-and BLOC-2-deficient human melanocytes Richmond et al, 2005), and enhanced cell surface flux of Tyrp1 in mouse melanocytes lacking AP-3, BLOC-1, or BLOC-2 (Di Pietro et al, 2006). We now show for the first time (to our knowledge) that BLOC-1-deficient melanocytes missort selected cargo destined for melanosomes from early endosomes.…”

Section: Discussionsupporting

confidence: 52%

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

Setty

Tenza

Truschel

et al. 2007

MBoC

199

342

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Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function.Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS. INTRODUCTIONHermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by hypopigmentation, prolonged bleeding, and sometimes ceroid accumulation, lung fibrosis, and/or immune defects leading to premature death Wei, 2006). HPS or a similar disorder in mice results from mutations in any of at least 15 genes (Wei, 2006). All of these genes are ubiquitously expressed, but their mutation in HPS affects mainly the generation and function of selected tissuespecific lysosome-related organelles (LROs;Bonifacino, 2004;Di Pietro and Dell'Angelica, 2005). Those LROs that are most severely affected in all forms of HPS-pigment cell melanosomes, platelet dense granules, and lung lamellar bodies-are unique in that they coexist with bona fide lysosomes in their respective cell types (Dell'Angelica et al., 2000;Marks and Seabra, 2001). The 15 known HPS-associated genes have been identified, and although the products of most are thought to participate in trafficking events that are uniquely required to form this class of LRO, the function of only a few is understood in detail.The genes disrupted in human HPS-7 (Li et al., 2003) and HPS-8 (Morgan et al., 2006) and in the mouse HPS models pallid, muted, reduced pigmentation (rp), cappuccino, and sandy encode five of the eight known subunits of a stable protein complex known as biogenesis of lysosome-related organelles complex (BLOC)-1 (Falcon-Perez et al., 2002;Moriyama and Bonifacino, 2002;Ciciotte et al., 2003;Li et al., 2003;Gwynn et al., 2004;Starcevic and Dell'Angelica, 2004). To date, no specific subcellular function has been assigned...

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Section: Discussionsupporting

confidence: 52%

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

Setty

Tenza

Truschel

et al. 2007

MBoC

199

342

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“…Mutations that affect LRO formation and/or function usually also affect pigmentation of melanocyte-containing tissues. The most obvious of these conditions is Hermansky-Pudlak syndrome (52), which has pleiotropic clinical effects (8). So far, eight distinct types of Hermansky-Pudlak syndrome have been identified, and all map to genes encoding proteins critical to protein trafficking (53).…”

Section: Disrupted Regulation Of Skin Pigmentationmentioning

confidence: 99%

The Regulation of Skin Pigmentation

Yamaguchi

Brenner

Hearing

2007

Journal of Biological Chemistry

414

344

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Visible pigmentation of the skin, hair, and eyes depends primarily on the functions of melanocytes, a very minor population of cells that specialize in the synthesis and distribution of the pigmented biopolymer melanin. Melanocytes are derived from precursor cells (called melanoblasts) during embryological development, and melanoblasts destined for the skin originate from the neural crest. The accurate migration, distribution, and functioning of melanoblasts/melanocytes determine the visible phenotype of organisms ranging from simple fungi to the most complex animal species. In human skin, melanocytes are localized at the dermal/epidermal border in a characteristic regularly dispersed pattern. Each melanocyte at the basal layer of the epidermis is functionally connected to underlying fibroblasts in the dermis and to keratinocytes in the overlying epidermis. Those three types of cells are highly interactive and communicate with each other via secreted factors and their receptors and via cell/cell contacts to regulate the function and phenotype of the skin. Overview: Architecture of the SkinEpidermal melanocytes occur at an approximate ratio of 1:10 among basal keratinocytes and distribute the melanin they produce to ϳ40 overlying suprabasal keratinocytes via their elongated dendrites and cell/cell contacts (presented schematically in Fig. 1). Although melanocytes and stem cell keratinocytes in the basal layer of the epidermis are very stable populations that proliferate extremely slowly under normal circumstances, keratinocytes in the upper layers of the epidermis proliferate relatively rapidly. That upward pressure carries them toward the surface of the skin along with their ingested melanin to form a critical barrier for the organism against the environment and the many stresses that originate there. Thus it is not the melanin within melanocytes only, but in combination with the pigment in more superficial layers, that gives skin its characteristic color. Although melanocytes in other locations of the body (e.g. hair follicles, eyes, inner ear, etc.) interact with surrounding cells in manners distinct from those in the epidermis, the basic processes involved in producing the melanin and the organelles within which it is synthesized (termed melanosomes) are comparable, as are the factors that regulate melanogenesis. This review will restrict itself to epidermal pigmentation, and readers interested in factors influencing pigmentation at other sites should consult recent reviews (1-6) and books (7, 8) on those topics.

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“…Interestingly, both lysosomal and melanosomal proteins depend on AP-1 and AP-3 for their trafficking, and it is not known how trafficking to these distinct organelles in melanocytes is distinguished. Additional components that influence Tyr and Tyrp1 trafficking to melanosomes include the biogenesis of lysosome-related organelles complex (BLOC)-1 and BLOC-2, subunits of which are defective in other forms of HPS, and the tissue-specific Rab proteins Rab32 and Rab38 (Richmond et al, 2005;Di Pietro et al, 2006;Wasmeier et al, 2006;Helip-Wooley et al, 2007;Setty et al, 2007). Tyrp1 and Tyr trafficking toward melanosomes or lysosomes is also regulated by lumenal interactions with glycosphingolipid-dependent membrane microdomains, presumably on endosomes (Sprong et al, 2001;GrouxDegroote et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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Oculocutaneous albinism type 2 is caused by defects in the gene OCA2, encoding a pigment cell-specific, 12-transmembrane domain protein with homology to ion permeases. The function of the OCA2 protein remains unknown, and its subcellular localization is under debate. Here, we show that endogenous OCA2 in melanocytic cells rapidly exits the endoplasmic reticulum (ER) and thus does not behave as a resident ER protein. Consistently, exogenously expressed OCA2 localizes within melanocytes to melanosomes, and, like other melanosomal proteins, localizes to lysosomes when expressed in nonpigment cells. Mutagenized OCA2 transgenes stimulate melanin synthesis in OCA2-deficient cells when localized to melanosomes but not when specifically retained in the ER, contradicting a proposed primary function for OCA2 in the ER. Steady-state melanosomal localization requires a conserved consensus acidic dileucine-based sorting motif within the cytoplasmic N-terminal region of OCA2. A second dileucine signal within this region confers steadystate lysosomal localization in melanocytes, suggesting that OCA2 might traverse multiple sequential or parallel trafficking routes. The two dileucine signals physically interact in a differential manner with cytoplasmic adaptors known to function in trafficking other proteins to melanosomes. We conclude that OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. INTRODUCTIONMelanin pigments are synthesized by specialized cell types, including dermal and epidermal melanocytes and retinal pigment epithelial cells, within unique organelles known as melanosomes . Melanosomes are members of a class of tissue-specific "lysosome-related organelles" characterized by an acidic lumenal pH and the presence of some lysosomal proteins (Dell'Angelica et al., 2000;Griffiths, 2002). Among lysosome-related organelles, melanosomes represent a subclass that coexists with bona fide lysosomes in their host cells . Melanosomes are distinguished from lysosomes by the presence of cell-type-specific cargo proteins that confer unique functional and morphological properties. How these cargo proteins are diverted from traditional lysosomes and delivered to and maintained within melanosomes is incompletely understood, and the degree of cargo cross-talk between melanosomes and lysosomes is not known.Melanosomes undergo a program of maturation within melanocytes by the ordered delivery of cargoes to nascent melanosomes via specialized trafficking pathways . Some components of the melanosomal trafficking machinery are known, largely from analyses of the sorting of well-characterized cargo proteins, such as the melanogenic enzyme tyrosinase (Tyr) and tyrosinase-related protein 1 (Tyrp1), in both wild-type melanocytes and melanocytes derived from patients or mouse models of genetic hypopigmentary diseases such as Hermansky-Pudlak Syndrome (HPS) (Di Pietro and Dell'Angelica, 2005;Wei, 2006). Tyr and Tyrp1 contain cytoplasmic a...

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Melanocytes Derived from Patients with Hermansky–Pudlak Syndrome Types 1, 2, and 3 Have Distinct Defects in Cargo Trafficking

Cited by 54 publications

References 54 publications

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

The Regulation of Skin Pigmentation

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

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