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

Setty, Subba Rao Gangi; Tenza, Danièle; Truschel, Steven T.; Chou, Evelyn; Sviderskaya, Elena V.; Theos, Alexander C.; Lamoreux, M. Lynn; Pietro, Santiago M. Di; Starcevic, Marta; Bennett, Dorothy C.; Dell’Angelica, Esteban C.; Raposo, Graça; Marks, Michael S.

doi:10.1091/mbc.e06-12-1066

Cited by 201 publications

(395 citation statements)

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“…BLOC-1 regulates membrane protein targeting to synaptic vesicles, lysosomes, and lysosome related organelles from transferrin-receptor-positive endosomes 62,[161][162] . Taking BLOC-1 as a starting point, Ryder and Faundez have reviewed the genetic literature for evidence supporting endosomal trafficking pathways in schizophrenia 23 , and conclude that an "endosomal hypothesis" accommodates the polygenetic nature of genetic association data as well as neurodevelopmental aspects of the disease.…”

Section: The Role Of Endosomal Traffickingmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane-and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the CME interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment are all influenced by CME, and that other cellular trafficking mechanisms previously linked to psychoses interact with CME in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of CME may offer fruitful opportunities for novel treatments of schizophrenia.

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Section: The Role Of Endosomal Traffickingmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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“…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%

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

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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“…These three proteins are components of the biogenesis of lysosome-related organelles complex 1 (BLOC-1), required for the proper sorting of cargo (such as TYRP1) from early endosomes to lysosome-related organelles 14 . In humans, mutations in dysbindin are associated with Hermansky-Pudlak Syndrome type 7 and with an increased susceptibility to schizophrenia 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Technical Note: The Use of RNA-interference as a Tool to Find Proteins Involved in Melanosome Formation or Transport

Amsen

Rotin

2009

Nature Precedings

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Abstract:Melanosomes are lysosome-related organelles that produce and transport the pigment melanin within melanocytes. Mutations in proteins required for melanosome transport and formation lead to a range of pigmentation defects, manifested at the cellular level as perinuclear clustering of melanosomes, or reduced sorting of melanosomal cargo such as tyrosinase-related protein 1 (TYRP1). A pilot screen was carried out to investigate whether a combination of cellular imaging and RNA interference could be used to identify new proteins involved in pigmentation pathways. In this study, eleven genes known to play a role in melanosome transport/formation or other pigmentation properties were knocked down in mouse melanocytes with shRNAmir constructs. The investigated genes were TYRP1, pallidin, cappuccino, dysbindin, HPS5, LYST, Myosin Va, melanophilin, RhoA, UBPY and mahogunin. In a blinded confocal imaging experiment, the only reproducible change observed in cells in which these targets were knocked down was a decrease in TYRP1 levels upon transfection with knockdown constructs against TYRP1 itself, or one of three constructs targeting HPS5 (Hermansky-Pudlak Syndrome 5). Upon analysis with high-content imaging software, only the knockdown construct against TYRP1 itself was detected. RT-PCR analysis showed that many of the shRNAmir constructs did not reduce mRNA and proteins levels enough to detect effects on melanosome properties. This was further examined for melanophilin, a protein necessary for melanosome transport. Altogether, the data show that this system is currently not sensitive enough for use in a screen for unknown regulators of melanosome transport and formation. The main obstacle appears to be incomplete reduction of target protein levels. Our observation that a ~50% reduction in mRNA level is not sufficient to elicit an effect is supported by the fact that heterozygous carriers of melanosomal transport disorders (Griscelli Syndrome, Hermansky-Pudlak Syndrome) do not display diseases phenotypes. A further reduction in protein levels, for example by viral integration of shRNA, may be required.

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

Cited by 201 publications

References 56 publications

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

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

Technical Note: The Use of RNA-interference as a Tool to Find Proteins Involved in Melanosome Formation or Transport

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