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bioRxiv · 10.1101/2021.02.05.430016

The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation

Koroma, D. C.·Scales, J. L.·Trotman, J. C.·Wakamatsu, K.·Ito, S.·Oancea, E.
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Abstract

Mutations in the Cl-/H+ exchanger CLC7 and its subunit OSTM1 result in osteopetrosis, lysosomal disorders, and pigmentation defects in mice and humans. How CLC7/OSTM1 regulates pigmentation in skin and hair melanocytes remains unexplored. In human epidermal melanocytes, we found CLC7/OSTM1 localized to melanosomes, the organelles in which melanin is synthesized, where it negatively regulates melanin production. Using a novel ratiometric melanosomal pH indicator, we showed that CLC7 acidifies melanosomes, opposing the function of the oculocutaneous albinism II (OCA2) Cl- ion channel. The de novo CLC7 variant (CLC7-Y715C) that causes albinism in humans and mice, decreased melanocytes pigmentation, which was restored by coexpression of OCA2. Remarkably, the enlarged hyperacidic vacuoles caused by CLC7-Y715C were also rescued by OCA2 coexpression in both melanocytes and non-melanocytic cells. Our data uncover a novel mechanism by which CLC7 regulates melanocyte pigmentation and identifies OCA2 as a tool to counteract the effects of CLC7 activating mutations.

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Koroma, D. C., Scales, J. L., Trotman, J. C., Wakamatsu, K., Ito, S., Oancea, E.. 2021-02-06. The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation. https://doi.org/10.1101/2021.02.05.430016

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