title: Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy.
abstract: Cystinosin, the lysosomal cystine exporter defective in cystinosis, is the founding member of a family of heptahelical membrane proteins related to bacteriorhodopsin and characterized by a duplicated motif termed the PQ loop. PQ-loop proteins are more frequent in eukaryotes than in prokaryotes; except for cystinosin, their molecular function remains elusive. In this study, we report that three yeast PQ-loop proteins of unknown function, Ypq1, Ypq2, and Ypq3, localize to the vacuolar membrane and are involved in homeostasis of cationic amino acids (CAAs). We also show that PQLC2, a mammalian PQ-loop protein closely related to yeast Ypq proteins, localizes to lysosomes and catalyzes a robust, electrogenic transport that is selective for CAAs and strongly activated at low extracytosolic pH. Heterologous expression of PQLC2 at the yeast vacuole rescues the resistance phenotype of an ypq2 mutant to canavanine, a toxic analog of arginine efficiently transported by PQLC2. Finally, PQLC2 transports a lysine-like mixed disulfide that serves as a chemical intermediate in cysteamine therapy of cystinosis, and PQLC2 gene silencing trapped this intermediate in cystinotic cells. We conclude that PQLC2 and Ypq1-3 proteins are lysosomal/vacuolar exporters of CAAs and suggest that small-molecule transport is a conserved feature of the PQ-loop protein family, in agreement with its distant similarity to SWEET sugar transporters and to the mitochondrial pyruvate carrier. The elucidation of PQLC2 function may help improve cysteamine therapy. It may also clarify the origin of CAA abnormalities in Batten disease.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Centre National de Recherche Scientifique, Unité Mixte de Recherche 8192, Centre Universitaire des Saints-Pères, F-75006 Paris, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Jézégou
authors.forename: Elisa
authors.initials: E
authors.lastname: Llinares
authors.forename: Christine
authors.initials: C
authors.lastname: Anne
authors.forename: Sylvie
authors.initials: S
authors.lastname: Kieffer-Jaquinod
authors.forename: Seana
authors.initials: S
authors.lastname: O'Regan
authors.forename: Joëlle
authors.initials: J
authors.lastname: Aupetit
authors.forename: Allel
authors.initials: A
authors.lastname: Chabli
authors.forename: Corinne
authors.initials: C
authors.lastname: Sagné
authors.forename: Cécile
authors.initials: C
authors.lastname: Debacker
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chadefaux-Vekemans
authors.forename: Agnès
authors.initials: A
authors.lastname: Journet
authors.forename: Bruno
authors.initials: B
authors.lastname: André
authors.forename: Bruno
authors.initials: B
authors.lastname: Gasnier
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D026923:Amino Acid Transport Systems, Basic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002172:Canavanine / Q000378:metabolism; D003543:Cysteamine / Q000627:therapeutic use*; D003554:Cystinosis / Q000188:drug therapy* / Q000378:metabolism*; D053487:DEAD-box RNA Helicases; D018076:DNA, Complementary / Q000235:genetics; D029721:Drosophila Proteins; D055724:Electrophysiological Phenomena; D005260:Female; D005800:Genes, Fungal; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014617:Vacuoles / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D026923:Amino Acid Transport Systems, Basic; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D029721:Drosophila Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C573925:SLC66A1 protein, human; D029701:Saccharomyces cerevisiae Proteins; C000598342:Ypq1 protein, S cerevisiae; D002172:Canavanine; D003543:Cysteamine; C107854:Hel25E protein, Drosophila; D053487:DEAD-box RNA Helicases