Functions of Adaptor Protein (AP)-3 and AP-1 in Tyrosinase Sorting from Endosomes to Melanosomes

Theos, Alexander C.; Tenza, Danièle; Martina, José A.; Hurbain, Ilse; Peden, Andrew A.; Sviderskaya, Elena V.; Stewart, Abigail; Robinson, Margaret S.; Bennett, Dorothy C.; Cutler, Daniel F.; Bonifacino, Juan S.; Marks, Michael S.; Raposo, Graça

doi:10.1091/mbc.e05-07-0626

Cited by 234 publications

(378 citation statements)

References 65 publications

(94 reference statements)

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“…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: 76%

“…The acidic dileucine signal in Tyr mediates an interaction with both AP-3 and AP-1 (Honing et al, 1998;Theos et al, 2005), whereas the corresponding signal in Tyrp1 has been shown to interact with AP-1 only (Theos et al, 2005). We therefore used an affinity "pull-down" assay to test whether the dileucine motifs in the OCA2 cytoplasmic domain can be recognized by heterotetrameric adaptors.…”

Section: Oca2 Binds Adaptors Ap-1 and Ap-3 In A Dileucinedependent Mamentioning

confidence: 99%

“…It is also possible that the combined activities of both human dileucine signals are incorporated into the single mouse dileucine signal, which differs in specific sequence from human LL1. Consistently, the single dileucine signal of tyrosinase seems to be sufficient to target tyrosinase to either of two distinct pathways to the melanosome (Theos et al, 2005;Setty et al, 2007). Although dileucine-based signals clearly play crucial roles in melanosomal trafficking, it is worth noting that none of the documented pathological point mutations in human Tyr, Tyrp1, or OCA2 occur in the acidic dileucine motifs of the proteins.…”

mentioning

confidence: 92%

“…Tyr and Tyrp1 contain cytoplasmic acidic dileucine motifs that are required for melanosomal sorting (Vijayasaradhi et al, 1995;Calvo et al, 1999;Simmen et al, 1999) and that are bound within endosomal intermediates by heterotetrameric adaptor proteins (APs) AP-1 or AP-3. 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).…”

Section: Introductionmentioning

confidence: 98%

“…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: 99%

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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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Section: Introductionmentioning

confidence: 76%

Section: Oca2 Binds Adaptors Ap-1 and Ap-3 In A Dileucinedependent Mamentioning

confidence: 99%

mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Molecular Genetics of Hermansky–Pudlak Syndrome

Cullinane

Huizing

Gahl

2013

Encyclopedia of Life Sciences

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Hermansky–Pudlak syndrome (HPS) is an autosomal recessive, genetically heterogeneous disorder characterised by oculocutaneous albinism and a bleeding diathesis. Subtype specific features such as neutropenic immunodeficiency and fatal lung fibrosis also occur. To date, nine human HPS subtypes (HPS‐1 to HPS‐9) and their associated genes have been identified. All of the HPS protein products are involved in biogenesis of lysosome‐related organelles (LROs) in specialised cells, including melanosomes in melanocytes and delta granules in platelets. The HPS proteins are all components of one of three biogenesis of lysosome‐related organelles complexes (BLOC‐1, BLOC‐2 or BLOC‐3) or the adaptor protein complex‐3. These complexes are essential for the correct formation of LROs, which are produced by the complex interaction of proteins, membranes and vesicles from the endocytic and biosynthetic pathways. Cells from patients with LRO disorders serve as useful tools for elucidating the complex pathways involved in the biogenesis of these organelles. Key Concepts: HPS is caused by mutations in nine known genes and is characterised by oculocutaneous albinism and a bleeding tendency. The proteins that are encoded by the HPS genes are all required for the correct formation of lysosome‐related organelles (LROs). LROs share features with lysosomes but have distinct morphology, composition and/or functions. LROs are maintained by the regulated flow of proteins, membranes and vesicles among the complex endosomal machinery. Novel players of LRO biogenesis are revealed by human disease and animal mutations, which continue to provide invaluable resources for elucidating the complex pathways involved in the biogenesis of these organelles.

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Lysosome‐Related Organelles: Modifications of the Lysosome Paradigm

Mantegazza

Marks

2016

Lysosomes: Biology, Diseases, and Therapeutics

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Functions of Adaptor Protein (AP)-3 and AP-1 in Tyrosinase Sorting from Endosomes to Melanosomes

Cited by 234 publications

References 65 publications

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

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

Molecular Genetics of Hermansky–Pudlak Syndrome

Lysosome‐Related Organelles: Modifications of the Lysosome Paradigm

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