Melanin Externalization in Candida albicans Depends on Cell Wall Chitin Structures
Claire WalkerBeatriz L. GómezHéctor M. Mora‐MontesK. MacKenzieCarol A. MunroAlistair J. P. BrownNeil A. R. GowChristopher C. KibblerFrank C. Odds
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ABSTRACT The fungal pathogen Candida albicans produces dark-pigmented melanin after 3 to 4 days of incubation in medium containing l -3,4-dihydroxyphenylalanine ( l -DOPA) as a substrate. Expression profiling of C. albicans revealed very few genes significantly up- or downregulated by growth in l -DOPA. We were unable to determine a possible role for melanin in the virulence of C. albicans . However, we showed that melanin was externalized from the fungal cells in the form of electron-dense melanosomes that were free or often loosely bound to the cell wall exterior. Melanin production was boosted by the addition of N -acetylglucosamine to the medium, indicating a possible association between melanin production and chitin synthesis. Melanin externalization was blocked in a mutant specifically disrupted in the chitin synthase-encoding gene CHS2 . Melanosomes remained within the outermost cell wall layers in chs3 Δ and chs2 Δ chs3 Δ mutants but were fully externalized in chs8 Δ and chs2 Δ chs8 Δ mutants. All the CHS mutants synthesized dark pigment at equivalent rates from mixed membrane fractions in vitro , suggesting it was the form of chitin structure produced by the enzymes, not the enzymes themselves, that was involved in the melanin externalization process. Mutants with single and double disruptions of the chitinase genes CHT2 and CHT3 and the chitin pathway regulator ECM33 also showed impaired melanin externalization. We hypothesize that the chitin product of Chs3 forms a scaffold essential for normal externalization of melanosomes, while the Chs8 chitin product, probably produced in cell walls in greater quantity in the absence of CHS2 , impedes externalization.Keywords:
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Cultured choroidal melanocytes from cattle were incubated with gold labeled albumin. After phagocytosis of the labeled protein, the label appeared inside the melanin granules, as was observed under the electron microscope. Melanin granules associated with gold particles were also exocytosed into the culture medium by the melanocytes. The results of this study show that endosomes or phagosomes are transported from the cell surface of a melanocyte to the melanin granules. Therefore, melanin granules are part of the lysosomal degradation pathway. The possibility that albumin is degraded by proteases present in lysosomes and melanosomes and that the tyrosine released during degradation is used as substrate by tyrosinase and thereby converted to melanin is discussed. The present study additionally shows that the choroidea of cattle can be used as a source for cell culture of melanocytes.
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The presence of melanin macroglobules, and sometimes that of melanosome complexes also, in epidermal melanocytes has been considered a feature of various skin diseases. Opinions differ as to whether these structures can occur in normal skin. We have studied these melanin inclusions in normal Caucasian skin in the entire soma of 116 melanocytes and the occurrence of melanosomes in phagosomes of 77 Langerhans' cells obtained in different seasons. During winter the melanocytes contained few melanosomes but many melanosome complexes and melanin macroglobules. These melanosome inclusions were in 86%, localized in the most basal part of the melanocytes, particularly in the dermal protrusions. It is suggested that these structures can be transferred from epidermal melanocytes to dermal cells and that melanin macroglobules derive from melanosome complexes. Irrespective of the season, most of the Langerhans' cells contained melanosomes in their phagosomes, which suggests a phagocytic capacity of these cells and a role in the elimination of the melanin.
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Lysosomes have reported that lysosomal intensity increased depending by aging. Lysosome and melanosome have some relations because melanosome has same producing pathway with lysosomes. Therefore we evaluated lysosomal intensity with efficiency of melanin reduction. We found that lysosomes can decrease the amount of melanin by their specialized functions in vivo . The melanin quantity compared in melanocytes after exposure to ultraviolet (UV) radiation and α -melanocyte stimulation hormone ( α -MSH) for evaluation expression level on different influence. Additionally, we compared the ability to reduce the amount of melanin after exposure to oxidative stress. Lastly we treated lysosomes isolated from HeLa cells to reduce melanin in melanocytes. 2% lysosomes were effective in reducing the amount of melanin in cells. Therefore, we conclude that lysosomes are a useful bio agent for decreasing the amount of melanin.
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Melanin incorporated into keratinocytes plays an important role in photoprotection; however, abnormal melanin accumulation causes hyperpigmentary disorders. To understand the mechanism behind the accumulation of excess melanin in the skin, it is essential to clarify the spatial distribution of melanosomes or melanin in the epidermis. Although several markers have been used to detect melanosomes or melanin, no suitable markers to determine the precise localization of melanin in the epidermis have been reported. In this study, we showed that melanocore-interacting Kif1c-tail (M-INK), a recently developed fluorescent probe for visualizing mature melanosomes, binds to purified melanin in vitro, and applied it for detecting melanin in human skin tissues. Frozen skin sections from different phototypes were co-stained for the hemagglutinin (HA)-tagged M-INK probe and markers of melanocytes or keratinocytes, and a wide distribution of melanin was observed in the epidermis. Analysis of the different skin phototypes indicated that the fluorescent signals of HA-M-INK correlated well with skin color. The reconstruction of three-dimensional images of epidermal sheets enabled us to observe the spatial distribution of melanin in the epidermis. Thus, the HA-M-INK probe is an ideal tool to individually visualize melanin (or melanosome) distribution in melanocytes and in keratinocytes in skin tissues.
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This study elucidates the nature of melanogenesis in B16 and Harding-Passey (HP) mouse melanomas producing melanin and melanosomes of different color and fine structure, i.e., brown-black eumelanosome-like B16 granules and reddish brown pheomelanosome-like HP granules, and compares them with "typical" 3,4-dihydroxyphenylalanine (DOPA) and sepia eumelanins and sepia eumelanosomes. The melanin content of B16 melanosomes was more than three times higher than that of HP melanosomes. 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. Chemical analysis of the eumelanin: pheomelanin ratio in melanosomes and elemental analysis of isolated melanin showed that B16 and HP melanins are primarily eumelanic, with a higher ratio of pheomelanic component in HP melanin. The spectra of electron spin resonance and IR and X-ray small-angle scattering of B16 and HP melanins were basically similar to those of sepia and DOPA melanins. B16, HP, and DOPA melanins were dissolved in aqueous NH3, while sepia melanin was dissolved to a far lesser extent. It was concluded that both B16 and HP melanomas are primarily involved in eumelanogenesis, although the fine structure of their melanosomes is entirely different, and that the marked color difference in the two melanosomes is related to a difference in the absolute content of eumelanin, the presence of a small amount of pheomelanin, and the mode of chemical bindings of melanin to structural proteins. In contrast to normal skin and hair, melanosome morphogenesis may not directly correspond to melanogenesis type in malignant melanoma.
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Skin Biology
Darker-skinned individuals have more melanin in their skin and a lower risk for skin cancers. The production of melanin in organelles called melanosomes is pH sensitive. Zhou et al. found that the enzymatic activity of soluble adenylyl cyclase (sAC) resulted in decreases in both melanosome pH and melanin synthesis. sAC deficiency or inhibitors increased melanosome pH and pigmentation in mice. This mechanism for rapidly regulating melanin synthesis could potentially be exploited to reduce skin cancer risk for fair-skinned individuals.
Sci. Signal. 11 , eaau7987 (2018).
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The key to diagnosing cases of melanoma, a tumor of melanocytes, is to recognize cytoplasmic pigment called melanin. In most cases this can be done at the light microscopy level; however, in the rarer amelanotic (non-pigmented) melanomas, melanin is not present in detectable amounts. Thus it is necessary to do an ultxastructural investigation to detect melanosomes, the specific organelles of the melanocyte that synthesize melanin. Other non-melanoma cells can also possess melanin by internalization of melanin granules by phagocytosis or passive transfer (e.g. macrophages, keratinocytes) but they lack the premelanosome organelle, the precursor to the fully developed melanosome. In premelanosomes, the internal structures are not obscured by melanin. Thus it is the diagnostic feature of choice for the pathologist. In malignant melanoma, aberrant forms of premelanosomes and melanosomes are more typical than in normal melanocytes., These aberrant forms may not be well recognized. Amelanotic melanomas give us a good opportunity to study these structures. In studying premelanosomes,the investigator must be aware of variations of size, shape, appearance in different planes of sections, and knowledge of the four stages of normal melanosome development (melanogenesis).
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A primary role of melanin in skin is the prevention of UV-induced nuclear DNA damage to human skin cells, where it serves to screen out harmful UV radiation. Melanin is delivered to keratinocytes in the skin after being excreted as melanosomes from melanocytes. Defects in melanin production in humans can cause diseases, many of which currently lack effective treatments due to their genetic origins (e.g., skin cancer, vitiligo, and albinism). The widespread prevalence of melanin-related diseases and an increasing interest in the performance of various polymeric materials related to melanin necessitates novel synthetic routes for preparing melanin-like materials. In this work, we prepared melanin-like nanoparticles (MelNPs) via spontaneous oxidation of dopamine, as biocompatible, synthetic analogues of naturally occurring melanosomes, and investigated their uptake, transport, distribution, and UV-protective capabilities in human keratinocytes. Critically, we demonstrate that MelNPs are endocytosed, undergo perinuclear aggregation, and form a supranuclear cap, or so-called microparasol in human epidermal keratinocytes (HEKa), mimicking the behavior of natural melananosomes in terms of cellular distribution and the fact that they serve to protect the cells from UV damage.
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