Abstract
Melanosomes are lysosome-related organelles that serve as specialized sites of melanin synthesis and storage in melanocytes. The progression of melanosomes through the different stages of their formation requires trafficking of specific proteins and membrane constituents in a sequential manner, which is likely to deploy ubiquitous cellular machinery along with melanocyte-specific proteins. Recent evidence revealed a connection between melanogenesis and the autophagy machinery, suggesting a novel role for members of the latter in melanocytes. Here we focused on ULK1, a key autophagy protein which is negatively regulated by mTORC1, to assess its potential role in melanogenesis in MNT-1 cells. We found that ULK1 depletion causes an increase in melanin levels, suggesting an inhibitory function for this protein in melanogenesis. Furthermore, this increase was accompanied by increased transcription of MITF (microphthalmia-associated transcription factor) and tyrosinase and by elevated protein levels of tyrosinase, the rate-limiting factor in melanin biogenesis. We also provide evidence to show that ULK1 function in this context is independent of the canonical ULK1 autophagy partners, ATG13 and FIP200. Furthermore we show that regulation of melanogenesis by ULK1 is independent of mTORC1 inhibition. Our data thus provide intriguing insights regarding the involvement of the key regulatory autophagy machinery in melanogenesis.
Highlights
Melanosomes are a type of Lysosome Related Organelle (LRO)
The recent discovery of a connection between melanogenesis and the autophagy machinery by Ganesan et al [13], and the proposed model by Ho et al suggesting that WIPI1 acts as a positive regulator of transcription through mTORC1 [14], led us to investigate the role of ULK1, a mTORC1-regulated autophagy protein, in melanogenesis
This delivery relies on membrane trafficking machinery that may overlap with other cellular pathways, in conjunction with melanocyte-specific proteins
Summary
Melanosomes are a type of Lysosome Related Organelle (LRO) As implied from their name, most LROs share some common features with lysosomes, such as an acidic lumenal pH and the presence of lysosomal proteins [1], LROs are unique to specific specialized cell types. Melanosome formation utilizes cellular trafficking machinery typically associated with other pathways, in conjunction with specific factors that provide organelle specificity and segregate them from other, more ubiquitous organelles An example of this comes from the study by Bultema et al, which shows that ubiquitous factors of lysosome biogenesis machinery, i.e. AP-1, AP-3 and BLOC-2, interact with the melanosome-specific proteins Rab and Rab to drive melanogenesis [8,9]
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