Molecular mechanisms of melanin transfer and processing by keratinocytes
Year: 2019
Type: dissertation
Abstract: The skin protects the human body against external aggressions, such as ultraviolet radiation (UVR) and microbial infections. Melanocytes and keratinocytes are the cell types most present in the skin epidermis and are essential to sustain skin pigmentation. Melanocytes synthesize the pigment melanin and are present at the basal layer of the epidermis. Keratinocytes are present in all the layers and are the final recipients of melanin, where it accumulates above the nuclei. Melanin sustains skin pigmentation and protects skin cells against UVR-induced damage, which can lead to the onset of skin cancer. Melanogenesis occurs in melanosomes, which share several features with lysosomes like low pH, the presence of lysosomal membrane proteins and catalytic enzymes and are thus considered lysosome-related organelles. Melanosome biogenesis is initiated at the perinuclear region, while mature melanosomes tend to accumulate at the tips of melanocyte dendrites. Once fully mature and located at the tips of melanocyte dendrites, melanosomes are transferred to keratinocytes. We found evidence that the predominant model of melanin transfer is coupled exo/endocytosis, where melanocytes exocytose the melanin core in a process dependent on the small GTPase Rab11b and the exocyst tethering complex and then internalized by keratinocytes. We also establish for the first time that melanocore internalization occurs through phagocytosis in a PAR-2-dependent manner. We conclude that the form of melanin presentation directly influences the internalization route followed by the pigment during internalization. Additionally, we determine that melanocores are stored within keratinocytes in maturation-arrested compartments that are not highly acid or highly degradative, allowing melanin to persist within the cell for long periods. Moreover, we observed that the capacity of the pigment to be recognized by PAR-2 might influence the way it is processed and if it can escape the degradative pathway. According to our data, melanocores but not melanosomes can avoid degradation within keratinocytes by modulating the autophagic flux. Thus, this study proposes a comprehensive model that links internalization and recognition of melanin at the plasma membrane with the determination of its fate and processing within keratinocytes in a PAR-2-regulated manner. Pigmentation disorders cause a significant reduction in the quality of life of those affected due to their social impact. Also, with the modern lifestyle, photoprotection has become a significant public health issue. Thus, this work has the potential to provide entirely new concepts in the field of skin pigmentation that can lead to the identification of novel regulators that can become drug targets for the pharma, biotech and cosmetic industries.
Author: Hugo Moreiras
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2996960211