Skin pigmentation is regulated by the synthesis of melanized melanosomes. The biogenesis of these melanosomes is an excellent model to explore the various molecular mechanisms that govern the chaperoning of gene products through the cytoplasm to distinct sites of action and/or organelles. One of these molecular mechanisms includes the Biogenesis of Lysosome-related Organelle Complex-2 (BLOC-2), which is ubiquitously expressed within all cell types. We have recently demonstrated that mutations in the genes that encode BLOC-2 components results in skin depigmentation characteristic of Hermansky-Pudlak Syndrome (HPS). We propose to test the hypothesis that BLOC-2 functions in the trafficking of tyrosinase related proteins (TRPs) to the melanosome and mutations affecting components of this complex correlate with translocational defects of the TRPs resulting in inefficient melanin synthesis in the melanosomes of HPS. This research will provide important insights into the understanding of cellular/molecular mechanisms governing trafficking in general and skin pigmentation in specific and pave the way for the development of potential therapeutic treatments for Hermansky-Pudlak Syndrome. Project Narrative: A subset of human genetic disease results from the inability of the affected cell or tissue to get the required gene product from its site of synthesis in the cell to its site of function elsewhere in the cell. This research will focus on a specific chaperone complex (BLOC- 2) that traffics melanocyte specific gene products to the melanosome organelle as a model to understand the molecular properties required for cellular trafficking that occur in all cells and to understand the pathophysiology underlying genetic diseases resulting from aberrant cellular trafficking.
| Chalupa, Allison; Koshoffer, Amy; Galan, Emily et al. (2015) Melanocytic galectin-3 is associated with tyrosinase-related protein-1 and pigment biosynthesis. J Invest Dermatol 135:202-211 |
