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

Autor: Sambri I; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy., Ferniani M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy., Campostrini G; Leiden University Medical Center, 2333ZC, Leiden, the Netherlands., Testa M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy., Meraviglia V; Leiden University Medical Center, 2333ZC, Leiden, the Netherlands., de Araujo MEG; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Dokládal L; Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland., Vilardo C; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy., Monfregola J; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy., Zampelli N; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy., Vecchio Blanco FD; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Ruosi C; Department of Translational Medical Sciences, University of Campania 'L. Vanvitelli', Naples, Italy., Fecarotta S; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy., Parenti G; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy., Staiano L; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy., Bellin M; Leiden University Medical Center, 2333ZC, Leiden, the Netherlands.; Department of Biology, University of Padua, 35131, Padua, Italy.; Veneto Institute of Molecular Medicine, 35129, Padua, Italy., Huber LA; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., De Virgilio C; Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland., Trepiccione F; Department of Translational Medical Sciences, University of Campania 'L. Vanvitelli', Naples, Italy.; Biogem Research Institute Ariano Irpino, Ariano Irpino, Italy., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy.; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Ballabio A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, (NA), Italy. ballabio@tigem.it.; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy. ballabio@tigem.it.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. ballabio@tigem.it.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA. ballabio@tigem.it.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 15; Vol. 14 (1), pp. 2775. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s41467-023-38428-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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