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The Journal of Biological Chemistry Aug 2023Niemann-Pick type C1 (NPC1) protein is a multimembrane spanning protein of the lysosome limiting membrane that facilitates intracellular cholesterol and sphingolipid...
Niemann-Pick type C1 (NPC1) protein is a multimembrane spanning protein of the lysosome limiting membrane that facilitates intracellular cholesterol and sphingolipid transport. Loss-of-function mutations in the NPC1 protein cause Niemann-Pick disease type C1, a lysosomal storage disorder characterized by the accumulation of cholesterol and sphingolipids within lysosomes. To investigate whether the NPC1 protein could also play a role in the maturation of the endolysosomal pathway, here, we have investigated its role in a lysosome-related organelle, the melanosome. Using a NPC1-KO melanoma cell model, we found that the cellular phenotype of Niemann-Pick disease type C1 is associated with a decreased pigmentation accompanied by low expression of the melanogenic enzyme tyrosinase. We propose that the defective processing and localization of tyrosinase, occurring in the absence of NPC1, is a major determinant of the pigmentation impairment in NPC1-KO cells. Along with tyrosinase, two other pigmentation genes, tyrosinase-related protein 1 and Dopachrome-tautomerase have lower protein levels in NPC1 deficient cells. In contrast with the decrease in pigmentation-related protein expression, we also found a significant intracellular accumulation of mature PMEL17, the structural protein of melanosomes. As opposed to the normal dendritic localization of melanosomes, the disruption of melanosome matrix generation in NPC1 deficient cells causes an accumulation of immature melanosomes adjacent to the plasma membrane. Together with the melanosomal localization of NPC1 in WT cells, these findings suggest that NPC1 is directly involved in tyrosinase transport from the trans-Golgi network to melanosomes and melanosome maturation, indicating a novel function for NPC1.
Topics: Humans; Melanosomes; Monophenol Monooxygenase; Niemann-Pick C1 Protein; Cholesterol; Niemann-Pick Diseases; Niemann-Pick Disease, Type C
PubMed: 37423302
DOI: 10.1016/j.jbc.2023.105024 -
Biochimica Et Biophysica Acta.... Dec 2020Melanosomes are unique organelles in melanocytes that produce melanin, the pigment for skin, hair, and eye color. Tyrosinase is the essential and rate-limiting enzyme... (Review)
Review
Melanosomes are unique organelles in melanocytes that produce melanin, the pigment for skin, hair, and eye color. Tyrosinase is the essential and rate-limiting enzyme for melanin production, that strictly requires neutral pH for activity. pH maintenance is a result of the combinational function of multiple ion transport proteins. Thus, ion homeostasis in melanosomes is crucial for melanin synthesis. Defect of the ion transport system causes various pigmentation phenotypes, from mild effect to severe disorders such as albinism. In this review, we summarize the up-to-date knowledge of the ion transport system, such as transport function, structure, and the physiological roles and mechanisms of the ion transport proteins in melanosomes. In addition, we propose a model of melanosomal ion transport system-how the functional coupling of multiple transport proteins modulates and maintains ion homeostasis. We discuss melanin synthesis in terms of the ion transport system.
Topics: Albinism, Oculocutaneous; Humans; Hydrogen-Ion Concentration; Ion Transport; Lysosomes; Melanins; Melanosomes; Membrane Transport Proteins; Monophenol Monooxygenase; Skin Pigmentation
PubMed: 32333855
DOI: 10.1016/j.bbamem.2020.183318 -
Experimental Dermatology Apr 2015
Topics: Humans; Melanoma; Melanosomes; Skin; Skin Neoplasms
PubMed: 25496715
DOI: 10.1111/exd.12618 -
F1000Research 2020Melanin pigments are responsible for human skin and hair color, and they protect the body from harmful ultraviolet light. The black and brown melanin pigments are... (Review)
Review
Melanin pigments are responsible for human skin and hair color, and they protect the body from harmful ultraviolet light. The black and brown melanin pigments are synthesized in specialized lysosome-related organelles called melanosomes in melanocytes. Mature melanosomes are transported within melanocytes and transferred to adjacent keratinocytes, which constitute the principal part of human skin. The melanosomes are then deposited inside the keratinocytes and darken the skin (a process called tanning). Owing to their dark color, melanosomes can be seen easily with an ordinary light microscope, and melanosome research dates back approximately 150 years; since then, biochemical studies aimed at isolating and purifying melanosomes have been conducted. Moreover, in the last two decades, hundreds of molecules involved in regulating melanosomal functions have been identified by analyses of the genes of coat-color mutant animals and patients with genetic diseases characterized by pigment abnormalities, such as hypopigmentation. In recent years, dynamic analyses by more precise microscopic observations have revealed specific functions of a variety of molecules involved in melanogenesis. This review article focuses on the latest findings with regard to the steps (or mechanisms) involved in melanosome formation and transport of mature melanosomes within epidermal melanocytes. Finally, we will touch on current topics in melanosome research, particularly on the "melanosome transfer" and "post-transfer" steps, and discuss future directions in pigment research.
Topics: Animals; Humans; Keratinocytes; Melanins; Melanocytes; Melanosomes; Skin; Skin Pigmentation
PubMed: 32595944
DOI: 10.12688/f1000research.24625.1 -
Pigment Cell & Melanoma Research Jul 2021Melanins are widely distributed in animals and plants; in vertebrates, most melanins are present on the body surface. The diversity of pigmentation in vertebrates is... (Review)
Review
Melanins are widely distributed in animals and plants; in vertebrates, most melanins are present on the body surface. The diversity of pigmentation in vertebrates is mainly attributed to the quantity and ratio of eumelanin and pheomelanin synthesis. Most natural melanin pigments in animals consist of both eumelanin and pheomelanin in varying ratios, and thus, their combined synthesis is called "mixed melanogenesis." Gene expression is an established mechanism for controlling melanin synthesis; however, there are multiple factors that affect melanin synthesis besides gene expression. Due to the differential sensitivity of the eumelanin and pheomelanin synthetic pathways to pH, melanosomal pH likely plays a major role in mixed melanogenesis. Here, we focused on various factors affecting mixed melanogenesis including (1) chemical regulation of melanin synthesis, (2) melanosomal pH regulation during normal melanogenesis and effect on mixed melanogenesis, and (3) mechanisms of melanosomal pH control (proton pumps, channels, transporters, and signaling pathways).
Topics: Animals; Cysteine; Humans; Kinetics; Melanins; Melanosomes; Monophenol Monooxygenase; Skin Pigmentation
PubMed: 33751833
DOI: 10.1111/pcmr.12970 -
International Journal of Molecular... Aug 2016In pigment cells, melanin synthesis takes place in specialized organelles, called melanosomes. The biogenesis and maturation of melanosomes is initiated by an... (Review)
Review
In pigment cells, melanin synthesis takes place in specialized organelles, called melanosomes. The biogenesis and maturation of melanosomes is initiated by an unpigmented step that takes place prior to the initiation of melanin synthesis and leads to the formation of luminal fibrils deriving from the pigment cell-specific pre-melanosomal protein (PMEL). In the lumen of melanosomes, PMEL fibrils optimize sequestration and condensation of the pigment melanin. Interestingly, PMEL fibrils have been described to adopt a typical amyloid-like structure. In contrast to pathological amyloids often associated with neurodegenerative diseases, PMEL fibrils represent an emergent category of physiological amyloids due to their beneficial cellular functions. The formation of PMEL fibrils within melanosomes is tightly regulated by diverse mechanisms, such as PMEL traffic, cleavage and sorting. These mechanisms revealed increasing analogies between the formation of physiological PMEL fibrils and pathological amyloid fibrils. In this review we summarize the known mechanisms of PMEL fibrillation and discuss how the recent understanding of physiological PMEL amyloid formation may help to shed light on processes involved in pathological amyloid formation.
Topics: Amyloid; Animals; Humans; Melanosomes; Protein Processing, Post-Translational; Protein Transport; Skin Pigmentation; gp100 Melanoma Antigen
PubMed: 27589732
DOI: 10.3390/ijms17091438 -
Traffic (Copenhagen, Denmark) Jun 2019Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the... (Review)
Review
Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.
Topics: Animals; Hermanski-Pudlak Syndrome; Humans; Lysosomes; Melanosomes; Weibel-Palade Bodies
PubMed: 30945407
DOI: 10.1111/tra.12646 -
Development (Cambridge, England) Oct 2023Neural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is...
Neural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is controlled. In mammals, the core gene regulatory network for melanocytes (their only pigment cell type) contains three transcription factors, Sox10, Pax3 and Mitf, with the latter considered a master regulator of melanocyte development. In teleosts, which have three to four pigment cell types (melanophores, iridophores and xanthophores, plus leucophores e.g. in medaka), gene regulatory networks governing fate specification are poorly understood, although Mitf function is considered conserved. Here, we show that the regulatory relationships between Sox10, Pax3 and Mitf are conserved in zebrafish, but the role for Mitf is more complex than previously emphasized, affecting xanthophore development too. Similarly, medaka Mitf is necessary for melanophore, xanthophore and leucophore formation. Furthermore, expression patterns and mutant phenotypes of pax3 and pax7 suggest that Pax3 and Pax7 act sequentially, activating mitf expression. Pax7 modulates Mitf function, driving co-expressing cells to differentiate as xanthophores and leucophores rather than melanophores. We propose that pigment cell fate specification should be considered to result from the combinatorial activity of Mitf with other transcription factors.
Topics: Animals; Gene Regulatory Networks; Mammals; Melanocytes; Mutation; Neural Crest; Oryzias; SOXE Transcription Factors; Zebrafish; Zebrafish Proteins
PubMed: 37823232
DOI: 10.1242/dev.202114 -
Experimental Dermatology Jul 2017In living cells, melanin pigment is formed within melanosomes, which not only protect the cells from autodestruction, but also serve as second messenger organelles...
In living cells, melanin pigment is formed within melanosomes, which not only protect the cells from autodestruction, but also serve as second messenger organelles regulating important skin functions, with melanocytes acting as primary sensory and regulatory cells of the epidermis. Yet, one can argue that skin melanin, which may negatively affect cellular homeostasis in melanoma, really exerts protective functions. Consequently, the actual functions of melanin and the melanogenic pathway in skin biology remains enigmatic. Yet, the solution of this riddle seems simple - to check the actual influence of natural melanin on skin cells in the dark. Since many interesting hypotheses and theories put forward in this respect did not survive confrontation with the experiment, a leading pigment research group from Naples was brave to "jump off the cliff" by confronting theory with experimental reality. They showed that, in the dark, human hair-derived melanin promotes inflammatory responses in keratinocytes, lowers their viability, promotes oxidative stress, and that pheomelanin does so more strongly than eumelanin. Thus, pheomelanin hardly protects red-haired individuals, even when avoiding the sun. Black hairs do not do much better either, unless they undergo graying.
Topics: Cell Survival; Darkness; Epidermis; Hair Color; Humans; Inflammation; Keratinocytes; Light; Melanins; Melanocytes; Melanosomes; Oxidative Stress; Skin; Skin Pigmentation
PubMed: 27541811
DOI: 10.1111/exd.13171 -
Developmental Biology May 2019Skin pigmentation is a powerful defense against ultraviolet irradiation. Particularly in humans, the body surface needs to be widely covered by protective pigmentation,... (Review)
Review
Skin pigmentation is a powerful defense against ultraviolet irradiation. Particularly in humans, the body surface needs to be widely covered by protective pigmentation, and melanocytes, a major lineage of neural crest derivatives, have evolved several maneuvers to transfer melanin pigment to the skin. Recent studies with embryonic melanocytes of chickens and mice have revealed sequential events mediated by melanocytes to maximize the skin coverage by pigmentation. These processes include the migration of melanocyte precursors in the embryo, the microscopic uniform spacing of individual melanocytes, and melanosome transfer from melanocytes to keratinocytes. In particular, in vivo/ex vivo live-imaging techniques of melanosome transfer and a quantitative method to evaluate the distribution patterns of melanocytes have greatly advanced our understanding of how a limited number of cells can implement a maximal coverage of the large surface area of a developing body.
Topics: Animals; Cell Movement; Chick Embryo; Chickens; Humans; Melanins; Melanocytes; Melanosomes; Mice; Models, Biological; Neural Crest; Skin Pigmentation
PubMed: 29698617
DOI: 10.1016/j.ydbio.2018.04.016