TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
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Published:2024-01-09
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Alesi NicolaORCID, Khabibullin Damir, Rosenthal Dean M., Akl Elie W., Cory Pieter M., Alchoueiry MichelORCID, Salem SamerORCID, Daou Melissa, Gibbons William F.ORCID, Chen Jennifer A.ORCID, Zhang Long, Filippakis Harilaos, Graciotti Laura, Miceli Caterina, Monfregola Jlenia, Vilardo ClaudiaORCID, Morroni Manrico, Di Malta Chiara, Napolitano GennaroORCID, Ballabio AndreaORCID, Henske Elizabeth P.ORCID
Abstract
AbstractTuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin’s benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference51 articles.
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