ArticleNature communications2023
RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- Rapidly Progressive Infantile Dilated Cardiomyopathy in Long-Olsen-Distelmaier Syndrome Associated withGenes · 2026Article
- RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- LncRNA FTX promotes myocardial fibrosis by sponging miR-335-3p to regulate TFEC/ILK signaling.Scientific reports · 2026Article
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis.Nature communications · 2025Article
- NovelKidney international reports · 2025Article
- Flufenamic acid inhibits pyroptosis in ischemic flaps via the AMPK-TRPML1-Calcineurin signaling pathway.Burns & trauma · 2025Article
- Ragopathies and the rising influence of RagGTPases on human diseases.Nature communications · 2024Review
- Tissue-specific expression differences in Ras-related GTP-binding proteins in male rats.Physiological reports · 2024Article
- The post-translational regulation of transcription factor EB (TFEB) in health and disease.EMBO reports · 2023Review
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Authors and funding
22 authors at 9 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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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