TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex

Nicola Alesi (), Damir Khabibullin, Dean M. Rosenthal, Elie W. Akl, Pieter M. Cory, Michel Alchoueiry, Samer Salem, Melissa Daou, William F. Gibbons, Jennifer A. Chen, Long Zhang, Harilaos Filippakis, Laura Graciotti, Caterina Miceli, Jlenia Monfregola, Claudia Vilardo, Manrico Morroni, Chiara Malta, Gennaro Napolitano, Andrea Ballabio () and Elizabeth P. Henske ()
Additional contact information
Nicola Alesi: Harvard Medical School
Damir Khabibullin: Harvard Medical School
Dean M. Rosenthal: Harvard Medical School
Elie W. Akl: Harvard Medical School
Pieter M. Cory: Harvard Medical School
Michel Alchoueiry: Harvard Medical School
Samer Salem: Harvard Medical School
Melissa Daou: Harvard Medical School
William F. Gibbons: Harvard Medical School
Jennifer A. Chen: Harvard Medical School
Long Zhang: Harvard Medical School
Harilaos Filippakis: Harvard Medical School
Laura Graciotti: Università Politecnica delle Marche
Caterina Miceli: Telethon Institute of Genetics and Medicine
Jlenia Monfregola: Telethon Institute of Genetics and Medicine
Claudia Vilardo: Telethon Institute of Genetics and Medicine
Manrico Morroni: Università Politecnica delle Marche
Chiara Malta: Telethon Institute of Genetics and Medicine
Gennaro Napolitano: Telethon Institute of Genetics and Medicine
Andrea Ballabio: Telethon Institute of Genetics and Medicine
Elizabeth P. Henske: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Tuberous 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.

Date: 2024
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DOI: 10.1038/s41467-023-44229-4

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