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The Journal of Cell Biology Nov 2022Melanosomes are pigment cell-specific lysosome-related organelles in which melanin pigments are synthesized and stored. Melanosome maturation requires delivery of...
Melanosomes are pigment cell-specific lysosome-related organelles in which melanin pigments are synthesized and stored. Melanosome maturation requires delivery of melanogenic cargoes via tubular transport carriers that emanate from early endosomes and that require BLOC-1 for their formation. Here we show that phosphatidylinositol-4-phosphate (PtdIns4P) and the type II PtdIns-4-kinases (PI4KIIα and PI4KIIβ) support BLOC-1-dependent tubule formation to regulate melanosome biogenesis. Depletion of either PI4KIIα or PI4KIIβ with shRNAs in melanocytes reduced melanin content and misrouted BLOC-1-dependent cargoes to late endosomes/lysosomes. Genetic epistasis, cell fractionation, and quantitative live-cell imaging analyses show that PI4KIIα and PI4KIIβ function sequentially and non-redundantly downstream of BLOC-1 during tubule elongation toward melanosomes by generating local pools of PtdIns4P. The data show that both type II PtdIns-4-kinases are necessary for efficient BLOC-1-dependent tubule elongation and subsequent melanosome contact and content delivery during melanosome biogenesis. The independent functions of PtdIns-4-kinases in tubule extension are downstream of likely redundant functions in BLOC-1-dependent tubule initiation.
Topics: 1-Phosphatidylinositol 4-Kinase; Endosomes; Intracellular Signaling Peptides and Proteins; Melanins; Melanocytes; Melanosomes; Phosphatidylinositol Phosphates; Protein Transport
PubMed: 36169639
DOI: 10.1083/jcb.202110114 -
Nicotine & Tobacco Research : Official... Aug 2006The role of melanin in nicotine uptake and metabolism has received little attention. Because nicotine has been shown to accumulate in tissues containing melanin,... (Review)
Review
The role of melanin in nicotine uptake and metabolism has received little attention. Because nicotine has been shown to accumulate in tissues containing melanin, exploring links between melanin and nicotine may provide additional clues to understanding smoking behavior and disease effects. To examine the scientific literature on the relationship between melanin and nicotine, we conducted a PubMed search. We also searched online archives of internal tobacco industry documents. We retrieved and reviewed 82 published research papers related to melanin and nicotine or melanin and metabolism of other drugs, and 150 relevant internal tobacco industry documents. The published literature suggests that nicotine may accumulate in human tissues containing melanin and this retention may increase melanin synthesis. Existing research on the relationship between melanin and nicotine lacks an adequate consideration of this relationship's potential impact, if any, on nicotine metabolism, level of nicotine dependence, and ability to quit smoking. Differential accumulation of nicotine in melanin-containing tissues could have implications for individuals with high levels of melanin.
Topics: Animals; Autoradiography; Carcinogens; Humans; Melanins; Melanosis; Melanosomes; Mice; Nicotine; Smoking Cessation; Nicotiana
PubMed: 16920646
DOI: 10.1080/14622200600790039 -
Proceedings of the National Academy of... May 2016Melanin is responsible for pigmentation of skin and hair and is synthesized in a specialized organelle, the melanosome, in melanocytes. A genome-wide association study...
Melanin is responsible for pigmentation of skin and hair and is synthesized in a specialized organelle, the melanosome, in melanocytes. A genome-wide association study revealed that the two pore segment channel 2 (TPCN2) gene is strongly linked to pigmentation variations. TPCN2 encodes the two-pore channel 2 (TPC2) protein, a cation channel. Nevertheless, how TPC2 regulates pigmentation remains unknown. Here, we show that TPC2 is expressed in melanocytes and localizes to the melanosome-limiting membrane and, to a lesser extent, to endolysosomal compartments by confocal fluorescence and immunogold electron microscopy. Immunomagnetic isolation of TPC2-containing organelles confirmed its coresidence with melanosomal markers. TPCN2 knockout by means of clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 gene editing elicited a dramatic increase in pigment content in MNT-1 melanocytic cells. This effect was rescued by transient expression of TPC2-GFP. Consistently, siRNA-mediated knockdown of TPC2 also caused a substantial increase in melanin content in both MNT-1 cells and primary human melanocytes. Using a newly developed genetically encoded pH sensor targeted to melanosomes, we determined that the melanosome lumen in TPC2-KO MNT-1 cells and primary melanocytes subjected to TPC2 knockdown is less acidic than in control cells. Fluorescence and electron microscopy analysis revealed that TPC2-KO MNT-1 cells have significantly larger melanosomes than control cells, but the number of organelles is unchanged. TPC2 likely regulates melanosomes pH and size by mediating Ca(2+) release from the organelle, which is decreased in TPC2-KO MNT-1 cells, as determined with the Ca(2+) sensor tyrosinase-GCaMP6. Thus, our data show that TPC2 regulates pigmentation through two fundamental determinants of melanosome function: pH and size.
Topics: Calcium; Calcium Channels; Cell Size; Humans; Hydrogen-Ion Concentration; Melanins; Melanosomes; Pigmentation
PubMed: 27140606
DOI: 10.1073/pnas.1600108113 -
Journal of Pharmacological Sciences Dec 2021Kaempferol, a representative flavonoid constituent of Sanguisorba officinalis, promotes melanogenesis, but the underlying mechanisms remain unknown. Here, we evaluated...
Kaempferol, a representative flavonoid constituent of Sanguisorba officinalis, promotes melanogenesis, but the underlying mechanisms remain unknown. Here, we evaluated the effects of kaempferol on melanocytes morphology and behavior and determined the mechanisms regulating kaempferol-induced pigmentation. We observed that kaempferol increased melanin contents and dendritic length and stimulated melanocyte migration both in vitro and vivo. It significantly enhanced the expression of microphthalmia-associated transcription factor (MITF) and downstream enzymes of melanin biosynthesis-tyrosinase (TYR), tyrosinase-related protein (TRP-1), and dopachrome tautomerase (DCT). It also induced melanosome maturation (increased stage III and IV melanosomes) and melanin transfer to dendritic tips; this was evidenced as follows: kaempferol-treated melanocytes exhibited the perimembranous accumulation of HMB45-positive melanosomes and increased the expression of Rab27A, RhoA, and Cdc42, which improved melanosome transport to perimembranous actin filaments. These results jointly indicated that kaempferol promotes melanogenesis and melanocyte growth. Additionally, kaempferol stimulated the phosphorylation of P38/ERK MAPK and downregulated p-PI3K, p-AKT, and p-P70s6K expression. Pre-incubation with P38 (SB203580) and ERK (PD98059) signaling inhibitors reversed the melanogenic and dendritic effects and MITF expression. PI3K/AKT inhibitor augmented kaempferol-induced melanin content and dendrite length. In summary, kaempferol regulated melanocytes' dendritic growth and melanosome quantity, maturation, and transport via P38/ERK MAPK and PI3K/AKT signaling pathways.
Topics: Animals; Biological Transport; Cell Line; Cell Movement; Kaempferols; MAP Kinase Signaling System; Melanins; Melanocytes; Melanosomes; Mice; Microphthalmia-Associated Transcription Factor; Phosphatidylinositol 3-Kinases; Pigmentation; Sanguisorba; Signal Transduction; Stimulation, Chemical; p38 Mitogen-Activated Protein Kinases
PubMed: 34663517
DOI: 10.1016/j.jphs.2021.08.009 -
Current Opinion in Cell Biology Dec 2020Melanocytes are neuroectoderm-derived pigment-producing cells with highly polarized dendritic morphology. They protect the skin against ultraviolet radiation by... (Review)
Review
Melanocytes are neuroectoderm-derived pigment-producing cells with highly polarized dendritic morphology. They protect the skin against ultraviolet radiation by providing melanin to neighbouring keratinocytes. However, the mechanisms underlying melanocyte polarization and its relevance for diseases remain mostly elusive. Numerous studies have instead revealed roles for polarity regulators in other neuroectoderm-derived lineages including different neuronal cell types. Considering the shared ontogeny and morphological similarities, these lineages may be used as reference models for the exploration of melanocyte polarity, for example, regarding dendrite formation, spine morphogenesis and polarized organelle transport. In this review, we summarize and compare the latest progress in understanding polarity regulation in neuronal cells and melanocytes and project key open questions for future work.
Topics: Cell Differentiation; Cell Lineage; Cell Polarity; Humans; Keratinocytes; Melanocytes; Melanosomes; Neural Plate
PubMed: 33099084
DOI: 10.1016/j.ceb.2020.09.001 -
Small GTPases 2013Lysosome-related organelles (LROs) exist in specialized cells to serve specific functions and typically co-exist with conventional lysosomes. The biogenesis of LROs is... (Review)
Review
Lysosome-related organelles (LROs) exist in specialized cells to serve specific functions and typically co-exist with conventional lysosomes. The biogenesis of LROs is known to utilize much of the common protein machinery used in the transport of integral membrane proteins to lysosomes. Consequently, an outstanding question in the field has been how specific cargoes are trafficked to LROs instead of lysosomes, particularly in cells that simultaneously produce both organelles. One LRO, the melanosome, is responsible for the production of the pigment melanin and has long been used as a model system to study the formation of specialized LROs. Importantly, melanocytes, where melanosomes are synthesized, are a cell type that also produces lysosomes and must therefore segregate traffic to each organelle. Two small GTPases, Rab32 and Rab38, are key proteins in the biogenesis of melanosomes and were recently shown to redirect the ubiquitous machinery-BLOC-2, AP-1 and AP-3-to traffic specialized cargoes to melanosomes in melanocytes. In addition, the study revealed Rab32 and Rab38 have both redundant and unique roles in the trafficking of melanin-producing enzymes and overall melanosome biogenesis. Here we review these findings, integrate them with previous knowledge on melanosome biogenesis and discuss their implications for biogenesis of other LROs.
Topics: Adaptor Protein Complex 1; Adaptor Protein Complex 3; Animals; Humans; Lysosomes; Melanins; Melanocytes; Melanosomes; Protein Transport; rab GTP-Binding Proteins
PubMed: 23247405
DOI: 10.4161/sgtp.22349 -
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 -
Experimental Dermatology Apr 2015
Topics: Humans; Melanoma; Melanosomes; Skin; Skin Neoplasms
PubMed: 25496715
DOI: 10.1111/exd.12618 -
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 -
Current Biology : CB Sep 2020At oceanic depths >200 m, there is little ambient sunlight, but bioluminescent organisms provide another light source that can reveal animals to visual predators and...
At oceanic depths >200 m, there is little ambient sunlight, but bioluminescent organisms provide another light source that can reveal animals to visual predators and prey [1-4]. Transparency and mirrored surfaces-common camouflage strategies under the diffuse solar illumination of shallower waters-are conspicuous when illuminated by directed bioluminescent sources due to reflection from the body surface [5, 6]. Pigmentation allows animals to absorb light from bioluminescent sources, rendering them visually undetectable against the dark background of the deep sea [5]. We present evidence suggesting pressure to reduce reflected bioluminescence led to the evolution of ultra-black skin (reflectance <0.5%) in 16 species of deep-sea fishes across seven distantly related orders. Histological data suggest this low reflectance is mediated by a continuous layer of densely packed melanosomes in the exterior-most layer of the dermis [7, 8] and that this layer lacks the unpigmented gaps between pigment cells found in other darkly colored fishes [9-13]. Using finite-difference, time-domain modeling and comparisons with melanosomes found in other ectothermic vertebrates [11, 13-21], we find the melanosomes making up the layer in these ultra-black species are optimized in size and shape to minimize reflectance. Low reflectance results from melanosomes scattering light within the layer, increasing the optical path length and therefore light absorption by the melanin. By reducing reflectance, ultra-black fish can reduce the sighting distance of visual predators more than 6-fold compared to fish with 2% reflectance. This biological example of efficient light absorption via a simple architecture of strongly absorbing and highly scattering particles may inspire new ultra-black materials.
Topics: Adaptation, Physiological; Animals; Biological Mimicry; Color; Fishes; Melanins; Melanosomes; Oceans and Seas; Skin Pigmentation
PubMed: 32679102
DOI: 10.1016/j.cub.2020.06.044