- Project PRIME (Molecular Mechanisms of Melanin Internalization and Processing by Keratinocytes)
01/10/2018 – 31/03/2022
Fundação para a Ciência e a Tecnologia
The skin is the largest organ of the human body and provides protection against external aggressions. The outmost layer, the epidermis is composed mainly by two cell types: melanocytes and keratinocytes. Melanocytes synthesize the pigment melanin and localize to the basal layer. Keratinocytes are present in all the layers and are the final recipients of melanin. Melanin protects skin cells against ultraviolet (UV) radiation-induced damage, which can lead to the onset of skin cancer. Melanin synthesis occurs in specialized organelles called 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. 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 the melanin core is exocytosed by melanocytes in a process dependent on the small GTPase Rab11b and the exocyst tethering complex, and then internalized by keratinocytes. Despite the crucial role of melanin uptake and processing by keratinocytes for skin pigmentation, the pathways involved have not been characterized. Moreover, after melanin is internalized by keratinocytes, little is known about how it accumulates at the supra-nuclear region of keratinocytes to shield the DNA from UV radiation. Therefore, we propose to study how melanin is internalized and processed by keratinocytes.
Objetives:
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- Investigate the internalization route followed by melanin in keratinocytes.
- Characterize the processing of melanin by keratinocytes.
- Determine the mechanism of melanin granule polarization within keratinocytes.
Our initial characterization suggests that melanin is stored in specialized endocytic compartments within keratinocytes that are not highly acidic or degradative, allowing it to resist degradation for long periods and remain during the process of differentiation towards the superficial layers of the stratified epithelium. This study has the potential to provide entirely new concepts in the field of skin pigmentation. Pigmentation disorders cause a reduction in the quality of life of those affected due to their social impact. Also, with the modern lifestyle, photoprotection has become an important issue. Thus, this work can also lead to the identification of novel key regulators that will become drug targets for the pharma, biotech and cosmetic industries.
Publications:
H. Moreiras, M.C. Seabra, D.C. Barral. “Melanin Transfer in the Epidermis: The Pursuit of Skin Pigmentation Control Mechanisms”. Int J Mol Sci. 2021 Apr 24;22(9):4466. doi: 10.3390/ijms22094466.
H. Moreiras, F.J.C. Pereira, M.V. Neto, L. Bento-Lopes, T.C. Festas, M.C. Seabra, D.C. Barral. "The exocyst is required for melanin exocytosis from melanocytes and transfer to keratinocytes". Pigment Cell Melanoma Res. 2020 Mar;33(2):366-371. doi: 10.1111/pcmr.12840
H. Moreiras, M. Lopes-da-Silva, M.C. Seabra, D.C. Barral. "Melanin processing by keratinocytes: A non-microbial type of host-pathogen interaction?". Traffic. 2019 Apr;20(4):301-304. doi: 10.1111/tra.12638.
Team:
Duarte Barral, Principal investigator
Miguel Seabra, co-Principal investigator
Abel Oliva, Investigator
João Pedro Vasconcelos, Investigator
Michael Hall, post-doctoral researcher
Liliana Bento-Lopes, PhD student