RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome
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 inhibi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38428-2 |
| _version_ | 1797822828931710976 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Irene Sambri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T10:13:55Z |
| format | Article |
| id | doaj.art-c0d4353e26904abf8698a54fb8a9d373 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:13:55Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c0d4353e26904abf8698a54fb8a9d3732023-05-21T11:20:19ZengNature PortfolioNature Communications2041-17232023-05-0114111310.1038/s41467-023-38428-2RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndromeIrene Sambri0Marco Ferniani1Giulia Campostrini2Marialuisa Testa3Viviana Meraviglia4Mariana E. G. de Araujo5Ladislav Dokládal6Claudia Vilardo7Jlenia Monfregola8Nicolina Zampelli9Francesca Del Vecchio Blanco10Annalaura Torella11Carolina Ruosi12Simona Fecarotta13Giancarlo Parenti14Leopoldo Staiano15Milena Bellin16Lukas A. Huber17Claudio De Virgilio18Francesco Trepiccione19Vincenzo Nigro20Andrea Ballabio21Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Leiden University Medical CenterTelethon Institute of Genetics and Medicine (TIGEM)Leiden University Medical CenterInstitute of Cell Biology, Biocenter, Medical University of InnsbruckDepartment of Biology, University of FribourgTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Department of Precision Medicine, University of Campania “Luigi Vanvitelli”Telethon Institute of Genetics and Medicine (TIGEM)Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”Medical Genetics Unit, Department of Medical and Translational Science, Federico II UniversityTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Leiden University Medical CenterInstitute of Cell Biology, Biocenter, Medical University of InnsbruckDepartment of Biology, University of FribourgDepartment of Translational Medical Sciences, University of Campania “L. Vanvitelli”Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)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.https://doi.org/10.1038/s41467-023-38428-2 |
| spellingShingle | 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 RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome Nature Communications |
| title | RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome |
| title_full | RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome |
| title_fullStr | RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome |
| title_full_unstemmed | RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome |
| title_short | RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome |
| title_sort | ragd auto activating mutations impair mit tfe activity in kidney tubulopathy and cardiomyopathy syndrome |
| url | https://doi.org/10.1038/s41467-023-38428-2 |
| work_keys_str_mv | AT irenesambri ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT marcoferniani ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT giuliacampostrini ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT marialuisatesta ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT vivianameraviglia ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT marianaegdearaujo ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT ladislavdokladal ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT claudiavilardo ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT jleniamonfregola ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT nicolinazampelli ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT francescadelvecchioblanco ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT annalauratorella ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT carolinaruosi ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT simonafecarotta ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT giancarloparenti ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT leopoldostaiano ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT milenabellin ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT lukasahuber ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT claudiodevirgilio ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT francescotrepiccione ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT vincenzonigro ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome AT andreaballabio ragdautoactivatingmutationsimpairmittfeactivityinkidneytubulopathyandcardiomyopathysyndrome |