{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:24:39Z","timestamp":1791206679160,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>\n                    Cystinosis is a rare autosomal recessive storage disorder characterized by defective lysosomal efflux of cystine due to mutations in the\n                    <jats:italic toggle=\"yes\">CTNS<\/jats:italic>\n                    gene encoding the lysosomal cystine transporter, cystinosin. Lysosomal cystine accumulation leads to crystal formation and functional impairment of multiple organs. Moreover, cystinosis is the most common inherited cause of renal Fanconi syndrome in children. Oral cysteamine therapy delays disease progression by reducing intracellular cystine levels. However, because cysteamine does not correct all complications of cystinosis, including Fanconi syndrome, we hypothesized that cystinosin could have novel roles in addition to transporting cystine out of the lysosome. By coimmunoprecipitation experiments and mass spectrometry, we found cystinosin interacts with almost all components of vacuolar H\n                    <jats:sup>+<\/jats:sup>\n                    -ATPase and the Ragulator complex and with the small GTPases Ras-related GTP-binding protein A (RagA) and RagC. Furthermore, the mammalian target of rapamycin complex 1 (mTORC1) pathway was downregulated in proximal tubular cell lines derived from\n                    <jats:italic toggle=\"yes\">Ctns\u2212\/\u2212<\/jats:italic>\n                    mice. Decrease of lysosomal cystine levels by cysteamine did not rescue mTORC1 activation in these cells, suggesting that the downregulation of mTORC1 is due to the absence of cystinosin rather than to the accumulation of cystine. Our results show a dual role for cystinosin as a cystine transporter and as a component of the mTORC1 pathway, and provide an explanation for the appearance of Fanconi syndrome in cystinosis. Furthermore, this study highlights the need to develop new treatments not dependent on lysosomal cystine depletion alone for this devastating disease.\n                  <\/jats:p>","DOI":"10.1681\/asn.2014090937","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T23:03:55Z","timestamp":1444345435000},"page":"1678-1688","source":"Crossref","is-referenced-by-count":98,"title":["Cystinosin is a Component of the Vacuolar H+-ATPase-Ragulator-Rag Complex Controlling Mammalian Target of Rapamycin Complex 1 Signaling"],"prefix":"10.1681","volume":"27","author":[{"given":"Zuzanna","family":"Andrzejewska","sequence":"first","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Nevo","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Thomas","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cerina","family":"Chhuon","sequence":"additional","affiliation":[{"name":"Proteomic Platform Necker (PPN), 3P5, SFR, Paris Descartes University, Faculty of Medicine, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bailleux","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Chauvet","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre J.","family":"Courtoy","sequence":"additional","affiliation":[{"name":"Cell Biology Unit, de Duve Institute, Universit\u00e9 Catholique de Louvain, Brussels, Belgium; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Chol","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Chiara","family":"Guerrera","sequence":"additional","affiliation":[{"name":"Proteomic Platform Necker (PPN), 3P5, SFR, Paris Descartes University, Faculty of Medicine, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Antignac","sequence":"additional","affiliation":[{"name":"French Institute of Health and Medical Research (INSERM) U1163, Laboratory of Hereditary Kidney Diseases, Paris, France;"},{"name":"Paris Descartes-Sorbonne Paris Cit\u00e9 University, Imagine Institute, Paris, France;"},{"name":"Department of Genetics, Necker Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,10,8]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.cell.2012.07.032","article-title":"Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1.","volume":"150","author":"Bar-Peled","year":"2012","journal-title":"Cell"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2010.02.024","article-title":"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.","volume":"141","author":"Sancak","year":"2010","journal-title":"Cell"},{"key":"B3-20230819","first-page":"1713","article-title":"Regulation of mTORC1 and its impact on gene expression at a 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