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Melanosomes Are Specialized Members of the Lysosomal Lineage of Organelles

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Melanosomes Are Specialized Members of the Lysosomal Lineage of Organelles REVIEW Melanosomes Are Specialized Members of the Lysosomal Lineage of Organelles Seth J. Orlow The Ronald 0. Perelman Department ofDem1atology and the Department of Cell Biology, New York University School of Medicine, N ew York, N ew York Melanosomes are specialized subcellular organelles nosomes, and has important implications for the in which melanin is synthesized and deposited. Elec­ chemistry of melanization and the potential phanna­ tron microscopic, cytochemical, genetic, and biochem­ cologic manipulation of that process. In addition, the ical evidence all support the contention that melano­ lysosome-like nature of melanosomes may provide somes are specialized lysosomes. The relationship of insight into the processing and presentation of mela­ melanosomes and lysosomes provides a framework in nosomal antigens by melanoma cells. Keywords: albi­ which to understand the pathogenesis of disorders such nismlretitral pigment epitlreliumltyrosinase. ] Invest DeJ'ttra­ as the Chediak-Higashi syndrome, allows the testing tol 105:3-7, 1995 of hypotheses for the trafficking of proteins to mela- elanin pigments are tyrosine-based biopolymers Beginning in the 19 50s, the e lectron m icroscope was used to synthesized and deposited within highly special­ generate much of our knowledge about the biogenesis of the ized subcellular organelles termed melano­ melanosome. There are four stages in the maturation of the somes. This review addresses the ontogeny of melanosome: stage I, the " premelanosome," a spherical organelle melanosomes. The evidence in support of a with ill-defin ed matrix filaments; stage II, in which the typical cMommon biogen etic pathway shared by melanosomes and the elliptical shape of the melanosome is .filled with a well-defined lysosomal lineage of organelles is reviewed. Melanosomes appear to filamentous or laminar matrix; stage Ill, with deposition of electron represent highly specialized lysosomes. opaque m elanin on tlus matrix; a nd stage IV, with complete The lysosome-like nature of melanosomes allows a large body of opacification of melanosomal con tents by the m elanin deposited knowledge accumulated from the study of lysosomes to be applied therein [3] . While under natural conditions melanin deposition is to pigment cell research. The biogenesis of lysosomes and the limited to stage III-IV melanosom es; cytochemical staining for the subcellular signals goveming the trafficking of proteins to lyso­ DOPA oxidase activity of tyrosinase reveals the presence of the somes are in large part well understood, and may hold true for enzym e in the Trans-Golgi network (TGN), i11 a population of melanosomes as well. The relationship of melanosomes to lyso­ coated vesicles, as well as stage I-II m elanosomes [4-6]. T he most somes provides a framework by which the pathogenesis of multi­ corrunonly accepted explanation for tlus observation involves a system disorders that affect both organelles, such as the Chediak­ bipartite pathway for melanosomal biogenesis. First, "premelano­ Higash.i and H ermansky-Pudlak syndromes, can be a ddressed. T he somes" containing i ncompletely o rganized matri.x buds from tl1e acidic nature oflysosome-like organelles predicts that melanization TGN, and the matrix subsequently condenses into its readily normally takes place under acidic conditions, and that pharmaco­ recognizable form as a stage II melanosome. Concurrently or logic manipulation of this acidification may allow us to modulate subsequently, c oated vesicles that contain tyrosinase arise from the the quantity and quality of melanin synthesized. Finally, the TGN. The fusion of these vesicles with the stage II melanosomes is lysosome-like nature of melanosomes may of!:er clues to the beli eved to initiate the process ofmelanogenesis [3,5]. Purification processing and presentation of melanosomal antigens by melanoma of subsets of coated vesicles from actively melanizing 1uelanoma cells. cells reveals that they have the expected high concentration of THE BIOGENESIS OF MELANOSOMES tyrosinase and m ehnun intem1ediates w itlun tl1em [7 ,8]. More than 40 years ago [1] it was recognized that tyrosinase, the MELANOSOMAL ACID PHOSPHATASE key melanogenic enzyme, existed in a particulate form. Subse­ By the late 1 960s cytochemical tecluuques allowed pigment cell quently, the subce llula.r organelle that functions as the site of researchers to investigate the distribution of other enzymes and melanin deposition was identified by Seiji and co-workers [2] and compare them with tyrosinase. Acid phosphatase activity is found in termed the melanosome. several acidic organelles, including not only 1ysosom es, but also portions of the Golgi apparatus and various specialized secretory granules. Miyamoto and Fitzpatrick [91 had shown the Reprint requests to: Seth]. Orlow, Department of Dermatology, H-100, presence of NYU Medical Center, 550 First Avenue, New York, NY 10016. acid phophatase within tl1e chick retinal pigment epithelium. Abbreviations: C H S, C hediak-Higashi syndrome; GERL, Golgi-endo­ Cytochemical staining for tl1 e activity of acid phosphatase revealed plasmic reticulum-lysosome; LAMP, lysosome-associated membrane pro­ its presence witllin melanosomes in bo tl1 mammalian and avian tein; TGN, T rans-Golgi network; T IL, tumor-infiltrating lymphocyte; melanocytes [10-12]. Furthermore, the identical distribution of TRP, ryrosinasc-related protein. tyrosinase and acid phosphatase within the GERL (Golgi-endoplas- 0022-202X/95/S09.50 • SSDI0022-202X(95)00216-8 • Copyright © 1995 by T he Society for Investigative Dermatology, Inc. 3 4 ORLOW THE JOURNAL OF INVESTIGATIVE DERMATOLOGY mic reticulum-lysosome) zone of che cell Jed Novikoff and co­ tions of an acidic intramelanosomal environment. Devi el a/ [31] workers [6] to conclude that melanosomes and lysosomes might had shown previously that pretreatment of murine tyrosinase at an share a common biogenetic pathway. acidic pH causes tl1e enzyme to lose the lag period that it normally demonstrates with tyrosine as a substrate in the absence of added GENETIC EVIDENCE FOR A MELANOLYSOSOMAL DOPA as cofactor. Subsequently, it became evident that this acidic RELATIONSHIP pH might have additional implications for the chemistry of mela­ Some of the earliest and most compelling evidence in support of a nization. For example, melanins rich in dillydrmryindole-2-carbox­ shared biogenetic relationship between melanosomes and lyso­ ylic acid are soluble at neutral pH but become progressively somes was provided by the study of genetic diseases affecting insoluble as the pH is lowered to 5 [32]. pigmentation in humans and mice. Chediak-Higashi syndrome If melanization indeed takes place in a lysosome-like acidic (CHS) is an autosomal recessive disorder in humans c haracterized organelle, then one might hypothesize that che modulation of by oculocutaneous albinism and immunodeficiency [13). Suscepti­ i.ntramelanosomal pH affords a means of modulating melanogenesis bility co a lymphoma-like phase, a bleeding diathesis, and neurop­ pharmacologically. Drugs that block the putative melanosomal athy are all well described associated phenomena. The microscopic proton-transporting ATPase, for example, might alter tl1e quantity haU.mark of CHS is the presence of giant granules in m any cell and and/or quality of melanin deposited therein. tissue types, including neutroph.ils, natural killer cells, melanocytes, fibroblasts, liver cells, etc [14,15). Studies at the light and electron MELANOSOMES ARE SPECIALIZED L YSOSOMES microscopic levels s uggested chat these giant granules arise by the aberrant fusion of these " lysosomally derived" organelles with one Although acid phosphatase and proton-translocating ATPase activ­ another. By contrast, a n additional organelle, the platelet-dense ities are present within melanosomes, the first protein formally granule, is either deficient or markedly reduced in those affected by proved to be shared by lysosomes and melanosomes was the CHS (16). lysosomal membrane glycoprotein Lamp-1 [33,34]. In addition, A second "melanolysosomal" disorder in humans is the Hennan­ Lamp-1 was identified in vesicles implicated in the trafficking of the sky-Pudlak syndrome [17]. In addition to the presence of oculocu­ tyrosinase-related protein family to melanosomes [34,35]. We have taneous albinism, persons affected by this autosomal recessive subsequently found that the related protein Lamp-2 is similarly disorder may suffer from a severe bleeding diathesis, interstitial distributed. pubnonary disease, and a granulomatous colitis. ln addition to the If melanosomes are indeed specialized lysosomes, then they absence of platelet-dense granules on electron microscopic exam­ might be predicted to contain a wide array oflysosomal hydrolases. ination [18), other typical findings include the accumulatiotJ. of a Smit and co-workers [36) studied extracts of human melanocytes ceroid-lipofuscin-like substance in the ly sosomes of macrophages subjected to density gradient fractionation and found that a portion in the lung and the gut [1 9]. ll1creased urinary dolichol excretion of tyrosinase co-migrated with the lysosomal hydrolase a-glucosi­ also supports a lysosomal involvement [20]. dase but was clearly separable from peroxisomal markers. By A third autosomal recessive disorder associated with both lyso­ combining cell fractionation techniques with the use of genetic somal and pigmentary abnormalities is in f.1 ntiJe sialic acid storage controls, we have recently demonstrated that melanosomes
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