Duncan NRI Faculty and Staff Publications
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
Published Open-Access
yes
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
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.
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