Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Adaptor Proteins, Signal Transducing/*metabolism ; Amino Acid Transport Systems, Neutral/*metabolism ; Cystinosis/*metabolism ; Lysosomal-Associated Membrane Protein 2/*metabolism ; Lysosomes/*metabolism ; rab GTP-Binding Proteins/*metabolism; Adaptor Proteins, Signal Transducing/genetics ; Amino Acid Substitution ; Amino Acid Transport Systems, Neutral/genetics ; Animals ; Cystinosis/genetics ; Cystinosis/pathology ; Enzyme Activators/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Expression Regulation, Enzymologic/genetics ; Lysosomal-Associated Membrane Protein 2/genetics ; Lysosomes/genetics ; Mice ; Mice, Knockout ; Point Mutation ; Protein Transport/genetics ; rab GTP-Binding Proteins/biosynthesis ; rab GTP-Binding Proteins/genetics ; rab7 GTP-Binding Proteins
    • Abstract:
      The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in Ctns -/- cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.
      (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
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    • Grant Information:
      R01 HL088256 United States HL NHLBI NIH HHS; P30 DK041296 United States DK NIDDK NIH HHS; R01 GM105894 United States GM NIGMS NIH HHS; P30 AG038072 United States AG NIA NIH HHS; P01 AG031782 United States AG NIA NIH HHS; R37 AG021904 United States AG NIA NIH HHS; R01 DK090058 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: autophagy; cell biology; lysosomal storage disease; lysosome; membrane trafficking
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Amino Acid Transport Systems, Neutral)
      0 (Enzyme Activators)
      0 (Lysosomal-Associated Membrane Protein 2)
      0 (Rilp protein, mouse)
      0 (cystinosin protein, mouse)
      0 (rab7 GTP-Binding Proteins)
      0 (rab7 GTP-binding proteins, mouse)
      EC 3.6.1.- (rab11 protein)
      EC 3.6.5.2 (rab GTP-Binding Proteins)
    • Publication Date:
      Date Created: 20170504 Date Completed: 20170705 Latest Revision: 20211204
    • Publication Date:
      20231215
    • Accession Number:
      PMC5481548
    • Accession Number:
      10.1074/jbc.M116.764076
    • Accession Number:
      28465352