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- Title
ERS1encodes a functional homologue of the human lysosomal cystine transporter.
- Authors
Xiao-Dong Gao; Ji Wang; Keppler-Ross, Sabine; Dean, Neta
- Abstract
Cystinosis is a lysosomal storage disease caused by an accumulation of insoluble cystine in the lumen of the lysosome.CTNSencodes the lysosomal cystine transporter, mutations in which manifest as a range of disorders and are the most common cause of inherited renal Fanconi syndrome. Cystinosin, theCTNSproduct, is highly conserved among mammals. Here we show that the yeast Ers1 protein and cystinosin are functional orthologues, despite sharing only limited sequence homology. Ers1 is a vacuolar protein whose loss of function results in growth sensitivity to hygromycin B. This phenotype can be complemented by the humanCTNSgene but not by mutantctnsalleles that were previously identified in cystinosis patients. A genetic screen for multicopy suppressors of aners1Δ yeast strain identified a novel gene,MEH1, which is implicated in regulating Ers1 function. Meh1 localizes to the vacuolar membrane and loss ofMEH1results in a defect in vacuolar acidification, suggesting that the vacuolar environment is critical for normalERS1function. This genetic system has also led us to identify Gtr1 as an Meh1 interacting protein. Like Meh1 and Ers1, Gtr1 associates with vacuolar membranes in an Meh1-dependent manner. These results demonstrate the utility of yeast as a model system for the study ofCTNSand vacuolar function.
- Subjects
CYSTINOSIS; RENAL tubular transport disorders; LYSOSOMES; FANCONI'S anemia; GENES; GENETICS; HOMOLOGY (Biology)
- Publication
FEBS Journal, 2005, Vol 272, Issue 10, p2497
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2005.04670.x