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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

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

Nicola Alesi1, Elie W Akl1, Damir Khabibullin1

  • 1Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Nature Communications
|July 13, 2021
PubMed

Insights

Tuberous Sclerosis Complex (TSC) involves mutations in TSC1/TSC2, leading to increased lysosomal biogenesis driven by Transcription Factor EB (TFEB). This study reveals TSC proteins regulate TFEB and RAGC, impacting cell proliferation.

Area of Science:

  • Cell Biology
  • Genetics
  • Biochemistry

Background:

  • Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes.
  • These mutations lead to the hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway.
  • Transcription Factor EB (TFEB) is a key regulator of lysosome biogenesis and is negatively controlled by mTORC1 through phosphorylation.

Purpose of the Study:

  • To investigate the role of TSC proteins in regulating lysosomal biogenesis.
  • To elucidate the mechanism by which TSC mutations affect TFEB activity.
  • To identify TFEB as a potential driver of cell proliferation in TSC.

Main Methods:

  • Analysis of lysosomal biogenesis in TSC-associated tissues and cells.
  • Assessment of TFEB phosphorylation status in TSC1/2-deficient cells.
  • Investigating the effect of folliculin (FLCN) and constitutively active RAGC on TFEB phosphorylation and localization.

Main Results:

  • Lysosomal biogenesis is elevated in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, and Tsc2+/- mouse kidneys.
  • TFEB is hypo-phosphorylated at mTORC1-dependent sites in TSC1/2-deficient cells.
  • Overexpression of FLCN increases TFEB phosphorylation, while active RAGC causes TFEB cytoplasmic relocalization.

Conclusions:

  • TSC proteins are critical regulators of lysosomal biogenesis through the TFEB and RAGC pathways.
  • TFEB is identified as a driver of proliferation in TSC2-deficient cells.
  • This provides new insights into the molecular mechanisms underlying TSC pathogenesis.

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