MFSD12 mediates the import of cysteine into melanosomes and lysosomes
Name
nihms-1624873.pdf
Description
Accepted version
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2.91 MB
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Checksum (MD5)
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Author(s)
Adelmann, Charles H
Traunbauer, Anna K
Chen, Brandon
Condon, Kendall J
Chan, Sze Ham
Kunchok, Tenzin
Lewis, Caroline A
Sabatini, David M
Date Issued
2020
Journal
Nature
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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 functions1,2. 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 humans3,4. 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 oxidation5,6. 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 cystinosin7–9. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/s41586-020-2937-x
