TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

Nicola Alesi, Elie W. Akl, Damir Khabibullin, Heng-Jia Liu, Anna S. Nidhiry, Emma R. Garner, Harilaos Filippakis, Hilaire C. Lam, Wei Shi, Srinivas R. Viswanathan, Manrico Morroni, Shawn M. Ferguson and Elizabeth P. Henske ()
Additional contact information
Nicola Alesi: Harvard Medical School
Elie W. Akl: Harvard Medical School
Damir Khabibullin: Harvard Medical School
Heng-Jia Liu: Harvard Medical School
Anna S. Nidhiry: Harvard Medical School
Emma R. Garner: Harvard Medical School
Harilaos Filippakis: Harvard Medical School
Hilaire C. Lam: Harvard Medical School
Wei Shi: University of Southern California
Srinivas R. Viswanathan: Harvard Medical School
Manrico Morroni: Università Politecnica delle Marche
Shawn M. Ferguson: Yale University School of Medicine
Elizabeth P. Henske: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). Transcription factor EB (TFEB), a master regulator of lysosome biogenesis, is negatively regulated by mTORC1 through a RAG GTPase-dependent phosphorylation. Here we show that lysosomal biogenesis is increased in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, kidneys from Tsc2+/− mice, and TSC1/2-deficient cells via a TFEB-dependent mechanism. Interestingly, in TSC1/2-deficient cells, TFEB is hypo-phosphorylated at mTORC1-dependent sites, indicating that mTORC1 is unable to phosphorylate TFEB in the absence of the TSC1/2 complex. Importantly, overexpression of folliculin (FLCN), a GTPase activating protein for RAGC, increases TFEB phosphorylation at the mTORC1 sites in TSC2-deficient cells. Overexpression of constitutively active RAGC is sufficient to relocalize TFEB to the cytoplasm. These findings establish the TSC proteins as critical regulators of lysosomal biogenesis via TFEB and RAGC and identify TFEB as a driver of the proliferation of TSC2-deficient cells.

Date: 2021
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DOI: 10.1038/s41467-021-24499-6

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