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Cystinosin, the protein defective in cystinosis, is a H + ‐driven lysosomal cystine transporter
Author(s) -
Kalatzis Vasiliki,
Cherqui Stéphanie,
Antignac Corinne,
Gasnier Bruno
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.21.5940
Subject(s) - cystinosis , cystine , biology , lysosomal storage disease , biochemistry , transmembrane domain , lysosome , microbiology and biotechnology , transport protein , extracellular , transporter , major facilitator superfamily , transmembrane protein , membrane transport , membrane , gene , cysteine , enzyme , receptor
Cystinosis is an inherited lysosomal storage disease characterized by defective transport of cystine out of lysosomes. However, the causative gene, CTNS , encodes a seven transmembrane domain lysosomal protein, cystinosin, unrelated to known transporters. To investigate the molecular function of cystinosin, the protein was redirected from lysosomes to the plasma membrane by deletion of its C‐terminal GYDQL sorting motif (cystinosin‐ΔGYDQL), thereby exposing the intralysosomal side of cystinosin to the extracellular medium. COS cells expressing cystinosin‐ΔGYDQL selectively take up L ‐cystine from the extracellular medium at acidic pH. Disruption of the transmembrane pH gradient or incubation of the cells at neutral pH strongly inhibits the uptake. Cystinosin‐ΔGYDQL is directly involved in the observed cystine transport, since this activity is highly reduced when the GYDQL motif is restored and is abolished upon introduction of a point mutation inducing early‐onset cystinosis. We conclude that cystinosin represents a novel H + ‐driven transporter that is responsible for cystine export from lysosomes, and propose that cystinosin homologues, such as mammalian SL15/Lec35 and Saccharomyces cerevisiae ERS1, may perform similar transport processes at other cellular membranes.