Abstract
Melanocytes are specialized cells that generate unique organelles called melanosomes in which melanin is synthesized and stored. Melanosome biogenesis and melanocyte pigmentation require the transport and delivery of melanin synthesizing enzymes, such as tyrosinase and related proteins (e.g., TYRP1), from endosomes to maturing melanosomes. Among the proteins controlling endosome-melanosome transport, AP-1 together with KIF13A coordinates the endosomal sorting and trafficking of TYRP1 to melanosomes. We identify here β1-adaptin AP-1 subunit-derived peptides of 5 amino acids that block the interaction of KIF13A with AP-1 in cells. Incubating these peptides with human MNT-1 cells or 3D-reconstructed pigmented epidermis decreases pigmentation by impacting the maturation of melanosomes in fully pigmented organelles. This study highlights that peptides targeting the intracellular trafficking of melanocytes are candidate molecules to tune pigmentation in health and disease.
Highlights
The skin plays a fundamental protective function against solar ultraviolet damage, preventing skin cancers such as melanoma
We report the design and effects of short adaptor protein (AP)-1-derived peptides that impair the interaction of KIF13A with the β1-adaptin subunit
Given that AP-1 and KIF13A function together along the same endosome-to-melanosome pathway required for pigmentation [6], we further investigated whether incubating pigment cells with those peptides could have an impact on the production of intracellular pigment in MNT-1 cells
Summary
The skin plays a fundamental protective function against solar ultraviolet damage, preventing skin cancers such as melanoma. Hydroquinone and its derivatives (e.g., hydrocortisone, arbutin, kojic acid) function as TYR inhibitors and decrease the melanin production by 20 to 50% in human normal melanocytes or melanoma cell lines in culture or skin equivalents. Of note, those molecules in combination do not show synergistic effects [13] and are often associated with cytotoxicity and side effects [12]. We report the design and effects of short AP-1-derived peptides that impair the interaction of KIF13A with the β1-adaptin subunit These peptides impair melanosome maturation and consistently reduce intracellular melanin production by MNT-1 cells (highly pigmented human non-metastatic melanoma cells) and by human pigmented synthetic epidermis. Such small molecules are certainly valuable candidates for modulating pigmentation
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