Disease relevance of Melanosomes

• Recent studies have shown that proteolysis by furin during secretion initiates both variant gelsolin amyloidogenesis, associated with the disease familial amyloidosis of Finnish type, and Pmel17 fiber formation, which is necessary for the functional biogenesis of melanosomes [1].
• In contrast, VPS33A induced significantly more clustering of melanosomes in melanoma cells than VPS33B [2].
• Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS) [3].
• Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding tendency and a ceroid-lipofuscin lysosomal storage disease result from defects of multiple cytoplasmic organelles: melanosomes, platelet dense granules and lysosomes [4].
• Inhibition of N-glycan processing in B16 melanoma cells results in inactivation of tyrosinase but does not prevent its transport to the melanosome [5].

High impact information on Melanosomes

• Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes [6].
• Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice [7].
• Some of the clones consisted of cells able to translocate their melanosomes in response to epinephrine, melatonin, or adenosine 3', 5'-monophosphate [8].
• Hermansky-Pudlak syndrome defines a group of genetic disorders characterized by defects in organelles of the endosomal-lysosomal system, most notably melanosomes and platelet-dense granules [9].
• Expression of siRNA-resistant Slp2-a (Slp2-a(SR)) rescued the peripheral dilution of melanosomes induced by Slp2-a siRNAs, but Slp2-a(SR) mutants, which failed to interact with either phospholipids or Rab27A, did not [10].

Chemical compound and disease context of Melanosomes

• Melanosomal "tyrosinase" (L-dopa) was isolated from trypsin digest of B-16 mouse melanoma melanosomes, using polyacrylamide gel disc electrophoresis [11].
• Selective aberration and pigment loss in melanosomes of malignant melanoma cells in vitro by glycosylation inhibitors: premelanosomes as glycoprotein [12].
• Antiserum raised in rabbits against the Triton X-100 insoluble fraction of melanosomes from mouse melanoma cells specifically decorates the internal matrix of melanosomes in immunoelectron microscopy [13].
• Electron microscopic dopa reaction has also revealed that these altered melanosomes seem to exhibit a weakly positive or a negative dopa reaction in both glucosamine- and tunicamycin-treated melanoma cells although a number of dopa-positive altered melanosomes are still seen [12].
• Rab3A as well as Rabphilin3A, a putative target protein of Rab3A, were detected in the melanosome fraction, purified from B16 murine melanoma cells by sucrose density gradient ultracentrifugation [14].

Biological context of Melanosomes

• Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis [15].
• These experiments show that the dilute myosin is necessary for the localization of melanosomes, either by active transport or tethering [16].
• However, in contrast to Gln78Leu, Trp73Gly mutant construct neither interacts with the Rab27a effector melanophilin nor modifies melanosome distribution and cytotoxic granule exocytosis [17].
• Unlike skin melanocytes, the effects of Rab27a are mediated through myosin VIIa in the RPE, as evidenced by the similar melanosome distribution phenotype observed in shaker-1 mice, defective in myosin VIIa [18].
• The melanosomal distribution of these enzymes was confirmed in studies of melanocytes cultured from albino mice and of melanocytes rendered amelanotic by transfection with the v-rasHa oncogene (which lack dense, melanized melanosomes) [19].

Anatomical context of Melanosomes

• Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles [20].
• A much slower dispersion (mean time of onset, 19.0 +/- 5.0 min) of melanosomes was observed when the microelectrode was positioned adjacent to a melanophore, and much larger quantities of cyclic AMP were released [21].
• We found that GM95 cells do not make melanin pigment because tyrosinase, the first and rate-limiting enzyme in melanin synthesis, was not targeted to melanosomes but accumulated in the Golgi complex [22].
• Taken together, these observations suggest that HPS1 and HPS4 are components of a protein complex that regulates the intracellular localization of lysosomes and late endosomes and may function in a BLOC-1-dependent pathway for melanosome biogenesis [23].
• However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation [24].

Associations of Melanosomes with chemical compounds

• The melanosome DNA could not be distinguished from nuclear and mitochondrial DNA by the amount of tritiated thymidine incorporated [25].
• Low-density sucrose fractions were found by electron microscopy to be enriched in stage I and stage II melanosomes, and these fractions were further separated and purified by free flow electrophoresis [26].
• In melanophores, light increases the intracellular level of inositol trisphosphate and causes the dispersion of melanosomes [27].
• The content of free and protein-bound DOPA and 5-S-cysteinyldopa varied greatly in B16, HP, and sepia melanosomes and was unrelated to melanin content [28].
• This transport system is critical to the function of the melanosome since tyrosine is the essential substrate required for the synthesis of the pigment melanin [29].

Gene context of Melanosomes

• Finally, transient expression in ashen melanocytes of Rab27a or Rab27b, but not other Rab's, restores peripheral distribution of melanosomes [30].
• Rab27a binds to the melanosome first and then recruits melanophilin, which in turn recruits myosin-Va [31].
• Western immunoblotting revealed that these catalytic proteins, as well as TYRP1, MART1, and GP100, were cleaved and inactivated in stage I melanosomes [26].
• We have recently shown that mouse melanosomes contain two electrophoretically distinct tyrosinase isoenzymes, termed low electrophoretic mobility tyrosinase (LEMT) and high electrophoretic mobility tyrosinase (HEMT), that can be resolved and purified [32].
• One interpretation of these observations is that Rab27a functions wholly or in part as the melanosome receptor for myosin Va (Myo5a) [33].

Analytical, diagnostic and therapeutic context of Melanosomes

• This, together with the plasma membrane occasional localization observed by immunofluorescence, suggest the TRP-2 participation in a recycling pathway, which could include or not the melanosomes [34].
• Some 70-80% of the myosin VIIa in RPE cells was detected on melanosome membranes by both subcellular fractionation of RPE cells and quantitative immunoelectron microscopy, consistent with a role for myosin VIIa in melanosome motility [35].
• Subcellular distribution of myosin V and proximity to actin bundles and melanosomes were determined by double indirect immunofluorescence labeling and immunogold electron microscopy [36].
• After treatment with all-trans retinoic acid, many of the cells became tyrosinase- and dihydroxyphenylalanine-reaction-positive, changed from polygonal to dendritic in shape, and had stage III to IV melanosomes [37].
• However, niacinamide gave 35-68% inhibition of melanosome transfer in the coculture model and reduced cutaneous pigmentation in the PREP model [38].

References