The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.

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  • Author(s): Luciani A;Luciani A; Devuyst O; Devuyst O; Devuyst O
  • Source:
    Autophagy [Autophagy] 2024 Jan; Vol. 20 (1), pp. 202-204. Date of Electronic Publication: 2023 Aug 24.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101265188 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8635 (Electronic) Linking ISSN: 15548627 NLM ISO Abbreviation: Autophagy Subsets: MEDLINE
    • Publication Information:
      Publication: 2015- : Philadelphia, PA : Taylor & Francis
      Original Publication: Georgetown, TX : Landes Bioscience, 2005-
    • Subject Terms:
      Amino Acid Transport Systems, Neutral*/metabolism ; Cystinosis*/metabolism; Artificial Intelligence ; Autophagy ; Cystine/metabolism ; Epithelial Cells/metabolism ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism
    • Abstract:
      Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.
    • References:
      Nat Commun. 2023 Jul 14;14(1):3994. (PMID: 37452023)
    • Contributed Indexing:
      Keywords: autophagy; chronic kidney disease; cystinosis; drug repurposing; lysosome; nutrient sensing
    • Accession Number:
      0 (Amino Acid Transport Systems, Neutral)
      48TCX9A1VT (Cystine)
      EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
    • Publication Date:
      Date Created: 20230825 Date Completed: 20240106 Latest Revision: 20240227
    • Publication Date:
      20240227
    • Accession Number:
      PMC10761040
    • Accession Number:
      10.1080/15548627.2023.2250165
    • Accession Number:
      37621073