Lysosome‐related organelles

Dell’Angelica, Esteban C.; Mullins, Chris; Caplan, Steve; Bonifacino, Juan S.

doi:10.1096/fasebj.14.10.1265

Cited by 335 publications

(338 citation statements)

References 124 publications

(138 reference statements)

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“…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 .…”

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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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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“…2 AP-3 mediates sorting of transmembrane proteins to lysosomes in all cells, but cells with secretory lysosomes, including melanocytes, platelets and leukocytes, are functionally impaired. [3][4][5][6][7] Previous studies of cytotoxic T-lymphocyte (CTL) clones from a patient with HPS2 (P1) showed decreased cytotoxicity and enlarged lytic granules that failed to polarize correctly towards target cells. 5 We now provide a description of 2 further unrelated individuals (P2 and P3) with HPS2 associated with novel mutations in AP3B1.…”

Section: Introductionmentioning

confidence: 99%

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

Wenham¹,

Grieve²,

Cummins³

et al. 2009

Haematologica

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“…1,2 The secretory lysosomes/primary granules of neutrophils are furnished with an array of proteins that includes hematopoietic serine proteases along with myeloperoxidase (MPO), other microbicidal proteins, and specific transmembrane proteins. 3,4 The precise functions of the hematopoietic serine proteases-neutrophil elastase (NE), cathepsin G, proteinase 3, and azurocidin-are not fully known, but all 4 are thought to be important in the innate immunity function provided by neutrophils.…”

Section: Introductionmentioning

confidence: 99%

The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

Källquist

Hansson

Persson

et al. 2008

Blood

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Targeting mechanisms of neutrophil elastase (NE) and other luminal proteins stored in myeloperoxidase (MPO)-positive secretory lysosomes/primary granules of neutrophils are unknown. These granules contain an integral membrane protein, CD63, with an adaptor protein-3-dependent granule delivery system. Therefore, we hypothesized that CD63 cooperates in granule delivery of the precursor of NE (proNE). Supporting this hypothesis, an association was demonstrated between CD63 and proNE upon coexpression in COS cells. This also involved augmented cellular retention of proNE requiring intact large extracellular loop of CD63. Furthermore, depletion of CD63 in promyelocytic HL-60 cells with RNA interference or a CD63 mutant caused reduction of cellular NE. However, the proNE steady-state level was similar to wild type in CD63-depleted clones, making it feasible to examine possible effects of CD63 on NE trafficking. Thus, depletion of CD63 led to reduced processing of proNE into mature NE and reduced constitutive secretion. Furthermore, CD63-depleted cells showed a lack of morphologically normal granules, but contained MPO-positive cytoplasmic vacuoles with a lack of proNE and NE. Collectively, our data suggest that granule proteins may cooperate in targeting; CD63 can be involved in ER or Golgi export, cellular retention, and granule targeting of proNE before storage as mature NE. (Blood. 2008;112:3444-3454) IntroductionHematopoietic cells play a critical role in host defense, for which they are equipped with secretory lysosomes or lysosome-related organelles that can release cell-specific cytolytic proteins by regulated secretion. 1,2 The secretory lysosomes/primary granules of neutrophils are furnished with an array of proteins that includes hematopoietic serine proteases along with myeloperoxidase (MPO), other microbicidal proteins, and specific transmembrane proteins. 3,4 The precise functions of the hematopoietic serine proteases-neutrophil elastase (NE), cathepsin G, proteinase 3, and azurocidin-are not fully known, but all 4 are thought to be important in the innate immunity function provided by neutrophils. 5,6 These proteases are synthesized as transient proforms that become catalytically active (except for azurocidin) by removal of an N-terminal propeptide after granule targeting. 7,8 Lysosome hydrolases and granzymes use a mannose-6-phosphate (MP) signal and binding to an MP receptor for targeting, 9,10 but the signals for the targeting of hematopoietic serine proteases are not yet known. Cargo proteins can be transported to secretory lysosomes independent of the MP system, 11 as is illustrated by the fact that in I-cell disease, neutrophils and other cells have a normal content of hydrolases despite a lack of MP synthesis. 12 The delivery of a soluble protein might occur through the assistance of a cooperating transmembrane partner that establishes contact with adaptor proteins (APs) to recruit the transport system necessary for targeting. The adaptor protein AP-3 is known to have a role in bringing transmembr...

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Lysosome‐related organelles

Cited by 335 publications

References 124 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

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

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