A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress
Abstract Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a cri...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-87107-3 |
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| author | Maja Bencun Laura Spreyer Etienne Boileau Jessica Eschenbach Norbert Frey Christoph Dieterich Mirko Völkers |
| author_facet | Maja Bencun Laura Spreyer Etienne Boileau Jessica Eschenbach Norbert Frey Christoph Dieterich Mirko Völkers |
| author_sort | Maja Bencun |
| collection | DOAJ |
| description | Abstract Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a critical regulator of cell growth, protein synthesis and autophagy mechanistic target of rapamycin complex 1 (mTORC1) is an important mediator of pathological cardiac remodeling. The tumor suppressor folliculin (FLCN) is part of the network regulating non-canonical mTORC1 activity. FLCN activates mTORC1 by functioning as a guanosine triphosphatase activating protein (GAP). Our work has identified a regulatory upstream open reading frame (uORF) localized in the 5′UTR of the FLCN mRNA. These small genetic elements are important regulators of protein expression. They are particularly important for the regulation of stress-responsive protein synthesis. We have studied the relevance of the FLCN uORF in the regulation of FLCN translation. We show that FLCN downregulation through the uORF is linked to cardiomyocyte growth and increased lysosomal activity. In summary, we have identified uORF-mediated control of RNA translation as another layer of regulation in the complex molecular network controlling cardiomyocyte hypertrophy. |
| format | Article |
| id | doaj-art-0ab110c080fc4cc28ffc829cd956c021 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0ab110c080fc4cc28ffc829cd956c0212025-02-02T12:16:24ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-025-87107-3A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stressMaja Bencun0Laura Spreyer1Etienne Boileau2Jessica Eschenbach3Norbert Frey4Christoph Dieterich5Mirko Völkers6Klaus Tschira Institute for Integrative Computational Cardiology, University of HeidelbergKlaus Tschira Institute for Integrative Computational Cardiology, University of HeidelbergKlaus Tschira Institute for Integrative Computational Cardiology, University of HeidelbergKlaus Tschira Institute for Integrative Computational Cardiology, University of HeidelbergDepartment of Cardiology, Angiology and Pneumology, University Hospital HeidelbergKlaus Tschira Institute for Integrative Computational Cardiology, University of HeidelbergDepartment of Cardiology, Angiology and Pneumology, University Hospital HeidelbergAbstract Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a critical regulator of cell growth, protein synthesis and autophagy mechanistic target of rapamycin complex 1 (mTORC1) is an important mediator of pathological cardiac remodeling. The tumor suppressor folliculin (FLCN) is part of the network regulating non-canonical mTORC1 activity. FLCN activates mTORC1 by functioning as a guanosine triphosphatase activating protein (GAP). Our work has identified a regulatory upstream open reading frame (uORF) localized in the 5′UTR of the FLCN mRNA. These small genetic elements are important regulators of protein expression. They are particularly important for the regulation of stress-responsive protein synthesis. We have studied the relevance of the FLCN uORF in the regulation of FLCN translation. We show that FLCN downregulation through the uORF is linked to cardiomyocyte growth and increased lysosomal activity. In summary, we have identified uORF-mediated control of RNA translation as another layer of regulation in the complex molecular network controlling cardiomyocyte hypertrophy.https://doi.org/10.1038/s41598-025-87107-3Hypertrophic growthUpstream open reading frameFolliculinTranslationTFEBLysosome |
| spellingShingle | Maja Bencun Laura Spreyer Etienne Boileau Jessica Eschenbach Norbert Frey Christoph Dieterich Mirko Völkers A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress Scientific Reports Hypertrophic growth Upstream open reading frame Folliculin Translation TFEB Lysosome |
| title | A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| title_full | A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| title_fullStr | A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| title_full_unstemmed | A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| title_short | A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| title_sort | novel uorf regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress |
| topic | Hypertrophic growth Upstream open reading frame Folliculin Translation TFEB Lysosome |
| url | https://doi.org/10.1038/s41598-025-87107-3 |
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