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RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome

Author

Listed:
  • Irene Sambri

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Marco Ferniani

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Giulia Campostrini

    (Leiden University Medical Center)

  • Marialuisa Testa

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Viviana Meraviglia

    (Leiden University Medical Center)

  • Mariana E. G. Araujo

    (Medical University of Innsbruck)

  • Ladislav Dokládal

    (University of Fribourg)

  • Claudia Vilardo

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Jlenia Monfregola

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Nicolina Zampelli

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Francesca Del Vecchio Blanco

    (University of Campania “Luigi Vanvitelli”)

  • Annalaura Torella

    (Telethon Institute of Genetics and Medicine (TIGEM)
    University of Campania “Luigi Vanvitelli”)

  • Carolina Ruosi

    (University of Campania “L. Vanvitelli”)

  • Simona Fecarotta

    (Federico II University)

  • Giancarlo Parenti

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Leopoldo Staiano

    (Telethon Institute of Genetics and Medicine (TIGEM)
    National Research Council (CNR))

  • Milena Bellin

    (Leiden University Medical Center
    University of Padua
    Veneto Institute of Molecular Medicine)

  • Lukas A. Huber

    (Medical University of Innsbruck)

  • Claudio Virgilio

    (University of Fribourg)

  • Francesco Trepiccione

    (University of Campania “L. Vanvitelli”
    Biogem Research Institute Ariano Irpino)

  • Vincenzo Nigro

    (Telethon Institute of Genetics and Medicine (TIGEM)
    University of Campania “Luigi Vanvitelli”)

  • Andrea Ballabio

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University
    Baylor College of Medicine
    Texas Children’s Hospital)

Abstract

Heterozygous mutations in the gene encoding RagD GTPase were shown to cause a novel autosomal dominant condition characterized by kidney tubulopathy and cardiomyopathy. We previously demonstrated that RagD, and its paralogue RagC, mediate a non-canonical mTORC1 signaling pathway that inhibits the activity of TFEB and TFE3, transcription factors of the MiT/TFE family and master regulators of lysosomal biogenesis and autophagy. Here we show that RagD mutations causing kidney tubulopathy and cardiomyopathy are “auto- activating”, even in the absence of Folliculin, the GAP responsible for RagC/D activation, and cause constitutive phosphorylation of TFEB and TFE3 by mTORC1, without affecting the phosphorylation of “canonical” mTORC1 substrates, such as S6K. By using HeLa and HK-2 cell lines, human induced pluripotent stem cell-derived cardiomyocytes and patient-derived primary fibroblasts, we show that RRAGD auto-activating mutations lead to inhibition of TFEB and TFE3 nuclear translocation and transcriptional activity, which impairs the response to lysosomal and mitochondrial injury. These data suggest that inhibition of MiT/TFE factors plays a key role in kidney tubulopathy and cardiomyopathy syndrome.

Suggested Citation

  • Irene Sambri & Marco Ferniani & Giulia Campostrini & Marialuisa Testa & Viviana Meraviglia & Mariana E. G. Araujo & Ladislav Dokládal & Claudia Vilardo & Jlenia Monfregola & Nicolina Zampelli & France, 2023. "RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38428-2
    DOI: 10.1038/s41467-023-38428-2
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    References listed on IDEAS

    as
    1. Zhicheng Cui & Gennaro Napolitano & Mariana E. G. Araujo & Alessandra Esposito & Jlenia Monfregola & Lukas A. Huber & Andrea Ballabio & James H. Hurley, 2023. "Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex," Nature, Nature, vol. 614(7948), pages 572-579, February.
    2. Gennaro Napolitano & Chiara Di Malta & Alessandra Esposito & Mariana E. G. de Araujo & Salvatore Pece & Giovanni Bertalot & Maria Matarese & Valerio Benedetti & Angela Zampelli & Taras Stasyk & Dilett, 2020. "A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome," Nature, Nature, vol. 585(7826), pages 597-602, September.
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