SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type IV (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with those expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes, SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic variant. Our data suggest 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.

SLC45A2编码一个主要在色素细胞中表达的推定转运蛋白。SLC45A2突变会引起IV型眼皮肤白化病（OCA4），而多态性与色素沉着变化有关，但SLC45A2及其变体的定位，功能和调控仍然未知。我们显示SLC45A2定位到一群成熟的黑素体，与表达氯化物通道OCA2的那些仅部分重叠。在HeLa细胞中异位表达的SLC45A2定位于溶酶体并提高了溶酶体pH，这表明在黑素细胞中，SLC45A2表达与OCA2表达一样，导致成熟的黑素体脱酸以支持黑色素的合成。有趣的是，OCA2过表达补偿了色素沉着中SLC45A2表达的损失。对SLC45A2和OCA2缺陷的小鼠黑素细胞的分析表明，SLC45A2可能在黑素体成熟期间比OCA2更晚发挥功能。此外，轻的皮肤相关SLC45A2等位基因F374变体由于蛋白酶体依赖性的快速降解而只能使SLC45A2缺乏的黑素细胞恢复中度色素沉着，从而导致黑素体中的蛋白质表达水平低于深色的皮肤相关等位基因变体。我们的数据表明，SLC45A2维持最初由瞬时OCA2活性精心策划的黑素体中和作用，以支持黑素体成熟后期的黑色素化，并且由于蛋白质的不稳定性，常见变体的活性降低。