RagD Auto-Activating Mutations Impair MIT/TFE Activity in Kidney Tubulopathy and Cardiomyopathy Syndrome

Authors

Irene Sambri
Marco Ferniani
Giulia Campostrini
Marialuisa Testa
Viviana Meraviglia
Mariana E G de 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 De Virgilio
Francesco Trepiccione
Vincenzo Nigro
Andrea Ballabio

Language

English

Publication Date

5-15-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-38428-2

PMID

37188688

PMCID

PMC10185561

PubMedCentral® Posted Date

5-15-2023

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, HeLa Cells, Induced Pluripotent Stem Cells, Kidney, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Mutation, Molecular biology, Mechanisms of disease, Genetics

Published Open-Access

yes

Recommended Citation

Sambri, Irene; Ferniani, Marco; Campostrini, Giulia; et al., "RagD Auto-Activating Mutations Impair MIT/TFE Activity in Kidney Tubulopathy and Cardiomyopathy Syndrome" (2023). Duncan NRI Faculty and Staff Publications. 32.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/32