Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nature. 2020 Dec;588(7839):699-704. doi: 10.1038/s41586-020-2937-x. Epub 2020 Nov 18.
Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
数十种基因导致了人类肤色的广泛差异。其中许多基因编码的蛋白质定位于黑素体——与溶酶体有关的细胞器，合成色素——但功能尚不清楚。在这里，我们描述了 MelanoIP，这是一种快速分离黑素体并分析其不稳定代谢物含量的方法。我们使用这种方法研究了 MFSD12，这是一种跨膜蛋白，其分子功能未知，当其被抑制时，会导致小鼠和人类的色素沉着更深。我们发现 MFSD12 是维持黑素体中半胱氨酸（半胱氨酸的氧化二聚体）正常水平所必需的，并且产生半胱氨酰多巴，这是通过半胱氨酸氧化在黑素体中合成的真黑色素合成的前体。示踪和生化分析表明，MFSD12 是将半胱氨酸导入黑素体所必需的，在非色素细胞中，是导入溶酶体所必需的。事实上，MFSD12 的缺失减少了胱氨酸在胱氨酸病患者成纤维细胞溶酶体中的积累，胱氨酸病是一种由溶酶体胱氨酸输出蛋白胱氨酸酶失活引起的溶酶体贮积病。因此，MFSD12 是黑素体和溶酶体半胱氨酸摄取器的重要组成部分。
