SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations and polymorphisms cause oculocutaneous albinism (OCA) and pigmentation variation, but neither SLC45A2 localization and function nor how gene variants affect these properties are known. We show that SLC45A2 localizes to mature melanosomes that only partially overlap with a cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that, like OCA2, SLC45A2 in melanocytes de-acidifies maturing melanosomes to support melanin synthesis. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 functions later during melanosome maturation than OCA2, and that OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. The light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes because of low level expression in melanosomes due to rapid proteasome-independent degradation. Our data indicate that SLC45A2 maintains melanosome neutralization – initially orchestrated by transient OCA2 activity – to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.