OCA7 is a melanosome membrane protein that defines pigmentation by regulating early stages of melanosome biogenesis.

Mutations in C10orf11 (oculocutaneous albinism type 7 [OCA7]) cause OCA, a disorder that presents with hypopigmentation in skin, eyes, and hair. The OCA7 pathophysiology is unknown, and there is virtually no information on the OCA7 protein and its cellular function. Here, we discover that OCA7 localizes to the limiting membrane of melanosomes, the specialized pigment cell organelles where melanin is synthesized. We demonstrate that OCA7 is recruited through interaction with a canonical effector-binding surface of melanosome proteins Rab32 and Rab38. Using newly generated OCA7-KO MNT1 cells, we show OCA7 regulates overall melanin levels in a melanocyte autonomous manner by controlling melanosome maturation. Importantly, we found that OCA7 regulates premelanosome protein (PMEL) processing, impacting fibrillation and the striations that define transition from melanosome stage I to stage II. Furthermore, the melanosome lumen of OCA7-KO cells displays lower pH than control cells. Together, our results reveal that OCA7 regulates pigmentation through two well-established determinants of melanosome biogenesis and function, PMEL processing, and organelle pH.

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3ß-mediated MITF degradation.