Glycoprotein nonmetastatic melanoma protein B: A key mediator and an emerging therapeutic target in autoimmune diseases

The glycoprotein nonmetastatic melanoma protein B (GPNMB, also known as osteoactivin) is highly expressed in many cell types and regulates the homeostasis in various tissues. In different physiological contexts, it functions as a melanosome- associated protein, membrane- bound surface receptor, soluble ligand, or adhesion molecule. Therefore, GPNMB is involved in cell differentiation, migration, inflammation, metabolism, and neuroprotection. Because of its various involvement in different physiological conditions, GPNMB has been implicated in many diseases, including cancer, neurological disorders, and more recently immune- mediated diseases. This review summarizes the regulation and function of GPNMB in normal physiology, and discusses the involvement of GPNMB in disease conditions with a particular focus on its potential role and therapeutic implications in autoimmunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155959/1/fsb220630.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155959/2/fsb220630_am.pd

Genetic Abnormalities, Melanosomal Transfer, and Degradation Inside Keratinocytes Affect Skin Pigmentation

Skin pigmentation is a specific and complex mechanism that occurs as a result of the quantity and quality of melanin produced, as well as the size, number, composition, mode of transfer, distribution, and degradation of the melanosomes inside keratinocytes and the handling of the melanin product by the keratinocyte consumer. Melanocyte numbers typically remain relatively constant. Melanin synthesis, melanosome maturation, and melanoblast translocation are considered to be responsible for hereditary pigmentary disorders. Keratinocytes play a significant role in regulating the adhesion, proliferation, survival, and morphology of melanocytes. In the epidermis, each melanocyte is surrounded by 30–40 keratinocytes through dendrites and transfers mature melanosomes into the cytoplasm of keratinocytes, which are then digested. Melanocytes are believed to transfer melanosomes to neighboring keratinocytes via exocytosis-endocytosis, microvesicle shedding, phagocytosis, or the fusion of the plasma membrane, protecting skin cells against ultraviolet (UV) damage by creating a physical barrier (cap structure) over the nucleus. An understanding of the factors of melanocytes and keratinocytes that induce pigmentation and the transfer mechanism of melanosomes to keratinocytes and how genetic abnormalities in keratinocytes affect pigmentary skin disorders will help us to elucidate hereditary pigmentary disorders more transparently and provide a conceptual framework for the importance of keratinocytes in the case of pigmentary disorders

A comprehensive review of mammalian pigmentation: paving the way for innovative hair colour-changing cosmetics

The natural colour of hair shafts is formed at the bulb of hair follicles, and it is coupled to the hair growth cycle. Three critical processes must happen for efficient pigmentation: (1) melanosome biogenesis in neural crest-derived melanocytes, (2) the biochemical synthesis of melanins (melanogenesis) inside melanosomes, and (3) the transfer of melanin granules to surrounding pre-cortical keratinocytes for their incorporation into nascent hair fibres. All these steps are under complex genetic control. The array of natural hair colour shades are ascribed to polymorphisms in several pigmentary genes. A myriad of factors acting via autocrine, paracrine, and endocrine mechanisms also contributes for hair colour diversity. Given the enormous social and cosmetic importance attributed to hair colour, hair dyeing is today a common practice. Nonetheless, the adverse effects of the long-term usage of such cosmetic procedures demand the development of new methods for colour change. In this context, case reports of hair lightening, darkening and repigmentation as a side-effect of the therapeutic usage of many drugs substantiate the possibility to tune hair colour by interfering with the biology of follicular pigmentary units. By scrutinizing mammalian pigmentation, this review pinpoints key targetable processes for the development of innovative cosmetics that can safely change the hair colour from the inside out.The authors thank the support of the Portuguese Foundation for Science and Technology (FCT), under the scope of the strategic funding of the UIDB/04469/2020 unit, and LABBELS— Associate Laboratory in Biotechnology, Bioengineering and Microelectromechnaical Systems, LA/P/ 0029/2020. The author Bruno Fernandes also acknowledges his PhD scholarship funded by FCT (SFRH/BD/131824/2017).info:eu-repo/semantics/publishedVersio

Research on Melanoma

The book Research on Melanoma: A Glimpse into Current Directions and Future Trends, is divided into sections to represent the most cutting-edge topics in melanoma from around the world. The emerging epigenetics of disease, novel therapeutics under development and the molecular signaling aberrations are explained in detail. Since there are a number of areas in which unknowns exist surrounding the complex development of melanoma and its response to therapy, this book illuminates and comprehensively discusses such aspects. It is relevant for teaching the novice researcher who wants to initiate projects in melanoma and the more senior researcher seeking to polish their existing knowledge in this area. Many chapters include visuals and illustrations designed to easily guide the reader through the ideas presented

The lipid droplet protein DHRS3 is a regulator of melanoma cell state

Lipid droplets are fat storage organelles composed of a protein envelope and lipid rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling

Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson's disease

During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion. The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes. The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems

Genetic basis of innovative anal fin pigmentation patterns in cichlid fish

The origination of novelty is one of the most fascinating questions in evolutionary biology. The repeated evolution of innovative pigmentation patterns on the anal fin in East African cichlid fish is an ideal model to study this question. One pattern is eggspots, the circular pigmentation pattern with a transparent outer ring that emerged once in the most species rich cichlid lineage, the haplochromines, exhibiting large varieties with different numbers, sizes and colours. Eggspots have been suggested to be involved in female attraction, male-male competition and species recognition. While ancestral haplochromine species feature another fin pigment trait in form of blotch, which is reddish with ill-defined boundary. Anal fin pigmentation pattern was also independently evolved in the ectodine lineage, which possesses similar blotch pattern as the haplochromine blotch. The ectodine blotch pattern was also suggested to be involved in female attraction, although less investigated. Unlike haplochromine eggspots, the ectodine blotch shows almost no variation among species. Here, by applying next generation sequencing technology (RNAseq and Ion Torrent sequencing) followed by a series data analysis, we found that haplochromine eggspots and the ectodine blotch share at least parts of a common gene network. Further sequencing data showed that many of the anal fin pigmentation related candidate genes have eggspots specific segregating patterns. While species with the blotch showed similar sequence patterns with species without anal fin pigmentation patterns. This might suggest that eggspots, but not the ectodine blotch, might have a much more independent gene network, which might explain its higher evolvability. Besides, we also described the evolutionary history of apolipoprotein D (ApoD) gene family in teleosts, whose expansion is via gene duplication and are located in two clusters in teleost fish. One member of this gene family was found to be highly expressed in the ectodine blotch. Interestingly, although most genes showed conserved homologous expression pattern in distant related teleosts, duplicated genes with new functions evolved in a lineage specific manner, especially in cichlid fish, and were expressed in two novelties, lower pharyngeal jaw and anal fin pigmentation. By investigating the genetic basis of the innovative anal fin pigmentation patterns in cichlid fish, this doctoral work gives clues about the relationship among evo-devo, novelty and biological diversity

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin