tailieunhanh - Báo cáo khoa học: ERS1 encodes a functional homologue of the human lysosomal cystine transporter

Cystinosis is a lysosomal storage disease caused by an accumulation of insoluble cystine in the lumen of the lysosome. CTNSencodes the lyso-somal 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 mam-mals. | ềFEBS Journal ERS1 encodes a functional homologue of the human lysosomal cystine transporter Xiao-Dong Gao1 Ji Wang2 Sabine Keppler-Ross2 and Neta Dean2 1 Research Center for Glycoscience National institute of Advanced Industrial science and Technology Tsukuba Japan 2 Department of Biochemistry and Cell Biology Institute for Celland DevelopmentalBiology State University of New York USA Keywords cystinosin ERS1 GTR1 MEH1 vacuole Correspondence N. Dean Department of Biochemistry and Cell Biology Institute for Celland DevelopmentalBiology State University of New York Stony Brook New York 117945215 USA Fax 1 631 632 8575 Tel 1 631 632 9309 E-mail Received 5 November 2004 revised 11 March 2005 accepted 18 March 2005 doi Cystinosis is a lysosomal storage disease caused by an accumulation of insoluble cystine in the lumen of the lysosome. CTNS encodes 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 the CTNS product 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 human CTNS gene but not by mutant ctns alleles that were previously identified in cysti-nosis patients. A genetic screen for multicopy suppressors of an erslD yeast strain identified a novel gene MEH1 which is implicated in regulating Ers1 function. Meh1 localizes to the vacuolar membrane and loss of MEH1 results in a defect in vacuolar acidification suggesting that the vacuolar environment is critical for normal ERS1 function. 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 .

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