title: Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells.
abstract: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease characterized by accumulation of cystine into lysosomes secondary to mutations in the cystine lysosomal transporter, cystinosin. The defect initially causes proximal tubular dysfunction (Fanconi syndrome) which in time progresses to end-stage renal disease. Cystinotic patients treated with the cystine-depleting agent, cysteamine, have improved life expectancy, delayed progression to chronic renal failure, but persistence of Fanconi syndrome. Here, we have investigated the role of the transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in conditionally immortalized proximal tubular epithelial cells derived from the urine of a healthy volunteer or a cystinotic patient. Lack of cystinosin reduced TFEB expression and induced TFEB nuclear translocation. Stimulation of endogenous TFEB activity by genistein, or overexpression of exogenous TFEB lowered cystine levels within 24 hours in cystinotic cells. Overexpression of TFEB also stimulated delayed endocytic cargo processing within 24 hours. Rescue of other abnormalities of the lysosomal compartment was observed but required prolonged expression of TFEB. These abnormalities could not be corrected with cysteamine. Thus, these data show that the consequences of cystinosin deficiency are not restricted to cystine accumulation and support the role of TFEB as a therapeutic target for the treatment of lysosomal storage diseases, in particular of cystinosis.
authors.affiliation: Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. Electronic address: laurarita.rega@opbg.net.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Rega
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Montefusco
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Napolitano
authors.affiliation: Unit for Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellomo
authors.affiliation: Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Taranta
authors.affiliation: Laboratory of Proteomics and Metabolomics, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.affiliation: Unit for Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Catz
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D003554:Cystinosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C111445:CTNS protein, human; C064972:TFEB protein, human; D003553:Cystine
keywords: cystinosis; pediatric nephrology; proximal tubule; renal pathology