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

Irene Sambri, Marco Ferniani, Giulia Campostrini, Marialuisa Testa, Viviana Meraviglia, Mariana E. G. Araujo, Ladislav Dokládal, Claudia Vilardo, Jlenia Monfregola, Nicolina Zampelli, Francesca Del Vecchio Blanco, Annalaura Torella, Carolina Ruosi, Simona Fecarotta, Giancarlo Parenti, Leopoldo Staiano, Milena Bellin, Lukas A. Huber, Claudio Virgilio, Francesco Trepiccione, Vincenzo Nigro and Andrea Ballabio ()
Additional contact information
Irene Sambri: Telethon Institute of Genetics and Medicine (TIGEM)
Marco Ferniani: Telethon Institute of Genetics and Medicine (TIGEM)
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)
Carolina Ruosi: University of Campania “L. Vanvitelli”
Simona Fecarotta: Federico II University
Giancarlo Parenti: Telethon Institute of Genetics and Medicine (TIGEM)
Leopoldo Staiano: Telethon Institute of Genetics and Medicine (TIGEM)
Milena Bellin: Leiden University Medical Center
Lukas A. Huber: Medical University of Innsbruck
Claudio Virgilio: University of Fribourg
Francesco Trepiccione: University of Campania “L. Vanvitelli”
Vincenzo Nigro: Telethon Institute of Genetics and Medicine (TIGEM)
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38428-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38428-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38428-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().