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Science (New York, N.Y.) Aug 2023Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering...
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.
Topics: Humans; Melanins; Melanocytes; Melanosomes; Skin Pigmentation; Genome-Wide Association Study; Adaptor Proteins, Signal Transducing; Kruppel-Like Factor 6; Endosomes; Animals; Mice; Cell Line, Tumor
PubMed: 37561850
DOI: 10.1126/science.ade6289 -
Cell Aug 2021Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated...
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Topics: Animals; Cell Line; Cohort Studies; Cyclic AMP; DNA Damage; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Melanocytes; Melanosomes; Mice; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor; Mitochondria; Monophenol Monooxygenase; NADP Transhydrogenases; Oxidation-Reduction; Polymorphism, Single Nucleotide; Proteasome Endopeptidase Complex; Proteolysis; RNA, Messenger; Skin Pigmentation; Ubiquitin; Ultraviolet Rays; Zebrafish
PubMed: 34233163
DOI: 10.1016/j.cell.2021.06.022 -
Nature Dec 2020Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the...
Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
Topics: Biological Transport; Cell Fractionation; Cell Line; Cysteine; Cystine; Cystinosis; Fibroblasts; Humans; Lysosomes; Melanins; Melanosomes; Membrane Proteins; Oxidation-Reduction
PubMed: 33208952
DOI: 10.1038/s41586-020-2937-x -
Acta Dermato-venereologica Jun 2020Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous... (Review)
Review
Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous melanoma cases are due to inherited variants or de novo mutations in approximately 20 genes, found using linkage, next-generation sequencing and association studies. Based on these studies, 3 classes of predisposing melanoma genes have been defined based on the frequency of the variants in the general population and lifetime risk of developing a melanoma: (i) ultra-rare variants with a high risk, (ii) rare with a moderate risk, and (iii) frequent variants with a low risk. Most of the proteins encoded by these genes have been shown to be involved in melanoma initiation, including proliferation and senescence bypass. This paper reviews the role(s) of these genes in the transformation of melanocytes into melanoma. It also describes their function in the establishment and renewal of melanocytes and the biology of pigment cells, if known.
Topics: Animals; Biomarkers, Tumor; Cell Lineage; Genetic Predisposition to Disease; Humans; Melanins; Melanocytes; Melanoma; Melanosomes; Mutation; Mutation Rate; Phenotype; Risk Assessment; Risk Factors; Skin Neoplasms; White People
PubMed: 32346747
DOI: 10.2340/00015555-3494 -
Trends in Ecology & Evolution May 2021Melanins are widespread pigments in vertebrates, with important roles in visual signaling, UV protection, and homeostasis. Fossil evidence of melanin and melanin-bearing... (Review)
Review
Melanins are widespread pigments in vertebrates, with important roles in visual signaling, UV protection, and homeostasis. Fossil evidence of melanin and melanin-bearing organelles - melanosomes - in ancient vertebrates may illuminate the evolution of melanin and its functions, but macroevolutionary trends are poorly resolved. Here, we integrate fossil data with current understanding of melanin function, biochemistry, and genetics. Mapping key genes onto phenotypic attributes of fossil vertebrates identifies potential genomic controls on melanin evolution. Taxonomic trends in the anatomical location, geometry, and chemistry of vertebrate melanosomes are linked to the evolution of endothermy. These shifts in melanin biology suggest fundamental links between melanization and vertebrate ecology. Tissue-specific and taxonomic trends in melanin chemistry support evidence for evolutionary tradeoffs between function and cytotoxicity.
Topics: Animals; Fossils; Melanins; Melanosomes; Pigmentation; Vertebrates
PubMed: 33549373
DOI: 10.1016/j.tree.2020.12.012 -
Cells Nov 2022Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic... (Review)
Review
Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
Topics: Humans; Arthrogryposis; Lysosomes; Melanosomes; Rare Diseases; Cholestasis; Kidney Diseases
PubMed: 36429129
DOI: 10.3390/cells11223702 -
The Journal of Experimental Biology Dec 2021Melanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating... (Review)
Review
Melanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating non-image forming visual behaviors, such as circadian photoentrainment and the pupillary light reflex, while also playing a role in many aspects of image-forming vision, such as contrast sensitivity. Melanopsin was initially discovered in the melanophores of the skin of the frog Xenopus, and subsequently found in a subset of ganglion cells in rat, mouse and primate retinas. ipRGCs were initially thought to be a single retinal ganglion cell population, and melanopsin was thought to activate a single, invertebrate-like Gq/transient receptor potential canonical (TRPC)-based phototransduction cascade within these cells. However, in the 20 years since the discovery of melanopsin, our knowledge of this visual pigment and ipRGCs has expanded dramatically. Six ipRGC subtypes have now been identified in the mouse, each with unique morphological, physiological and functional properties. Multiple subtypes have also been identified in other species, suggesting that this cell type diversity is a general feature of the ipRGC system. This diversity has led to a renewed interest in melanopsin phototransduction that may not follow the canonical Gq/TRPC cascade in the mouse or in the plethora of other organisms that express the melanopsin photopigment. In this Review, we discuss recent findings and discoveries that have challenged the prevailing view of melanopsin phototransduction as a single pathway that influences solely non-image forming functions.
Topics: Animals; Light Signal Transduction; Mice; Rats; Retina; Retinal Ganglion Cells; Rod Opsins
PubMed: 34842918
DOI: 10.1242/jeb.226522 -
Cells Jun 2022Pigmentation is an important process in skin physiology and skin diseases and presumably also plays a role in Parkinson's disease (PD). In PD, alpha-Synuclein (aSyn) has...
Pigmentation is an important process in skin physiology and skin diseases and presumably also plays a role in Parkinson's disease (PD). In PD, alpha-Synuclein (aSyn) has been shown to be involved in the pigmentation of neurons. The presynaptic protein is intensively investigated for its pathological role in PD, but its physiological function remains unknown. We hypothesized that aSyn is both involved in melanocytic differentiation and melanosome trafficking processes. We detected a strong expression of aSyn in human epidermal melanocytes (NHEMs) and observed its regulation in melanocytic differentiation via the microphthalmia-associated transcription factor (MITF), a central regulator of differentiation. Moreover, we investigated its role in pigmentation by performing siRNA experiments but found no effect on the total melanin content. We discovered a localization of aSyn to melanosomes, and further analysis of aSyn knockdown revealed an important role in melanocytic morphology and a reduction in melanosome release. Additionally, we found a reduction of transferred melanosomes in co-culture experiments of melanocytes and keratinocytes but no complete inhibition of melanosome transmission. In summary, this study highlights a novel physiological role of aSyn in melanocytic morphology and its so far unknown function in the pigment secretion in melanocytes.
Topics: Humans; Keratinocytes; Melanins; Melanocytes; Melanosomes; alpha-Synuclein
PubMed: 35805172
DOI: 10.3390/cells11132087 -
Cells Jun 2022Melanosomes are melanocyte-specific organelles that protect cells from ultraviolet (UV)-induced deoxyribonucleic acid damage through the production and accumulation of... (Review)
Review
Melanosomes are melanocyte-specific organelles that protect cells from ultraviolet (UV)-induced deoxyribonucleic acid damage through the production and accumulation of melanin and are transferred from melanocytes to keratinocytes. The relatively well-known process by which melanin is synthesized from melanocytes is known as melanogenesis. The relationship between melanogenesis and autophagy is attracting the attention of researchers because proteins associated with autophagy, such as WD repeat domain phosphoinositide-interacting protein 1, microtubule-associated protein 1 light chain 3, autophagy-related (ATG)7, ATG4, beclin-1, and UV-radiation resistance-associated gene, contribute to the melanogenesis signaling pathway. Additionally, there are reports that some compounds used as whitening cosmetics materials induce skin depigmentation through autophagy. Thus, the possibility that autophagy is involved in the removal of melanin has been suggested. To date, however, there is a lack of data on melanosome autophagy and its underlying mechanism. This review highlights the importance of autophagy in melanin homeostasis by providing an overview of melanogenesis, autophagy, the autophagy machinery involved in melanogenesis, and natural compounds that induce autophagy-mediated depigmentation.
Topics: Autophagy; Homeostasis; Melanins; Melanocytes; Melanosomes
PubMed: 35805169
DOI: 10.3390/cells11132085 -
Integrative and Comparative Biology Oct 2021Melanins, the main pigments of the skin and hair in mammals, are synthesized within membrane-bound organelles of melanocytes called melanosomes. Melanosome structure and... (Review)
Review
Melanins, the main pigments of the skin and hair in mammals, are synthesized within membrane-bound organelles of melanocytes called melanosomes. Melanosome structure and function are determined by a cohort of resident transmembrane proteins, many of which are expressed only in pigment cells and localize specifically to melanosomes. Defects in the genes that encode melanosome-specific proteins or components of the machinery required for their transport in and out of melanosomes underlie various forms of ocular or oculocutaneous albinism, characterized by hypopigmentation of the hair, skin, and eyes and by visual impairment. We review major components of melanosomes, including the enzymes that catalyze steps in melanin synthesis from tyrosine precursors, solute transporters that allow these enzymes to function, and structural proteins that underlie melanosome shape and melanin deposition. We then review the molecular mechanisms by which these components are biosynthetically delivered to newly forming melanosomes-many of which are shared by other cell types that generate cell type-specific lysosome-related organelles. We also highlight unanswered questions that need to be addressed by future investigation.
Topics: Animals; Mammals; Melanins; Melanocytes; Melanosomes; Pigmentation
PubMed: 34021746
DOI: 10.1093/icb/icab078