AP-3 Mediates Tyrosinase but Not TRP-1 Trafficking in Human Melanocytes

Huizing, Marjan; Sarangarajan, Rangaprasad; Strovel, Erin T.; Zhao, Yang; Gahl, William A.; Boissy, Raymond E.

doi:10.1091/mbc.12.7.2075

Cited by 146 publications

(179 citation statements)

References 51 publications

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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: 53%

“…Despite these observations, neither the pathway by which BLOC-1-dependent cargoes travel nor the specific transport step regulated by BLOC-1 is known. Furthermore, although BLOC-1 interacts physically with two other protein complexes-BLOC-2 and adaptor protein (AP)-3-that are defective in different forms of HPS (Di Pietro et al, 2006), and AP-3 regulates cargo transport in melanocytes (Huizing et al, 2001;Theos et al, 2005), a functional link between these complexes has not been well established. Here, we exploit primary and immortalized melanocytes from HPS model mice to identify a vesicular transport step regulated by BLOC-1 that is required for trafficking of selected cargo from early endosomes to maturing melanosomes.…”

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confidence: 99%

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

Setty

Tenza

Truschel

et al. 2007

MBoC

201

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: 53%

mentioning

confidence: 99%

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

Setty

Tenza

Truschel

et al. 2007

MBoC

201

342

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“…Instead of having two acidic amino acids in the − 5 and − 4 positions relative to the di-leucines, Tyrp1 has a single acidic residue. This may account for the failure of AP-3-deficient melanocytes of patients with Hermansky-Pudlak 2 (HPS2) to manifest an alteration in Tyrp1 collateral to the abnormal trafficking of tyrosinase in these mutant melanocytes (53). Consistent with this is the observation by Hö ning et al (52) demonstrating that when the −5 amino acid of LIMP II is substituted by an A, as occurs naturally in Tyrp1, interaction with AP-3 is abrogated.…”

Section: Tyrp1 the Proteinmentioning

confidence: 79%

Tyrp1 and Oculocutaneous Albinism Type 3

Sarangarajan

Boissy

2001

Pigment Cell Research

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addition to its role in eumelanin synthesis, Tyrp1 is involved in Tyrosinase-related protein 1 (Tyrp1) is a melanocyte-specific maintaining stability of tyrosinase protein and modulating its gene product involved in eumelanin synthesis. Mutations in the catalytic activity. Tyrp1 is also involved in maintenance of mouse Tyrp1 gene are associated with brown pelage, and in the human TYRP1 gene with oculocutaneous albinism type 3 melanosome ultrastructure and affects melanocyte prolifera-(OCA3). In the murine system, Tyrp1 expresses significant tion and melanocyte cell death. The current review is an dihydroxyindole carboxylic acid oxidase (i.e. DHICA oxattempt to consolidate our understanding of the role of Tyrp1 idase) activity. However, in humans, TYRP1 is enigmatic in in the melanocyte. that despite extensive efforts focused on the study of its Key words: Pigmentation, Tyrosine hydroxylase, Brown/Rufunction, its actual role in the human melanocyte is still fous Albinism, Brown locus, Protein trafficking unclear. There is mounting evidence demonstrating that in Mutations in the genes encoding some of the enzymes and regulatory proteins involved in melanin synthesis result in various forms of oculocutaneous albinism (OCA). OCA1 correlates with mutations in the tyrosinase (TYR) gene (7). Most individuals with OCA1 have completely amelanotic skin, hair and eyes with the inability to tan (i.e. OCA1A). However, some nucleotide lesions of the TYR gene result in a partially functional enzyme so that individuals with this subtype of OCA1 can exhibit moderate levels of skin and hair pigmentation and the ability to tan (i.e. OCA1B). OCA2 correlates with mutations in the P gene (8). Individuals with OCA2 present with minimal to moderate amounts of pigment remaining in the skin, hair and eyes, many of whom can develop pigmented freckles, lentigines and/or nevi with age. OCA3 correlates with mutations in the TYRP1 gene (9). Individuals with OCA3 present with minimal pigment reduction in the skin, hair and eyes. This form of albinism was previously referred to as Rufous and possibly some forms of Brown albinism.

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“…AP-1 and AP-3 each bind the Tyr sorting signal (Honing et al, 1998;Theos et al, 2005), but they participate in distinct delivery pathways toward melanosomes (Theos et al, 2005). Consistently, Tyr is largely (but not completely) missorted in melanocytes derived from human HPS type 2 patients and HPS model pearl mice that bear mutations in the gene encoding the ␤3A subunit of AP-3 (Huizing et al, 2001;Theos et al, 2005). By contrast, the acidic dileucine-based sorting signal in Tyrp1 has been shown to bind AP-1 but not AP-3 (Theos et al, 2005), and accordingly Tyrp1 accumulates normally on melanosomes in AP-3-deficient melanocytes (Huizing et al, 2001;Setty et al, 2007) (although an unusually large cohort cycles through the plasma membrane; Di Pietro et al, 2006).…”

Section: Introductionmentioning

confidence: 87%

“…Consistently, Tyr is largely (but not completely) missorted in melanocytes derived from human HPS type 2 patients and HPS model pearl mice that bear mutations in the gene encoding the ␤3A subunit of AP-3 (Huizing et al, 2001;Theos et al, 2005). By contrast, the acidic dileucine-based sorting signal in Tyrp1 has been shown to bind AP-1 but not AP-3 (Theos et al, 2005), and accordingly Tyrp1 accumulates normally on melanosomes in AP-3-deficient melanocytes (Huizing et al, 2001;Setty et al, 2007) (although an unusually large cohort cycles through the plasma membrane; Di Pietro et al, 2006). These results corroborate the dependence on AP-1 and AP-3, respectively, for in vitro budding of Tyrp1 and tyrosinase from Golgi/endosomal membrane fractions (Chapuy 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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AP-3 Mediates Tyrosinase but Not TRP-1 Trafficking in Human Melanocytes

Cited by 146 publications

References 51 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

Tyrp1 and Oculocutaneous Albinism Type 3

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

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