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TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1

Christian C Dibble1, Winfried Elis, Suchithra Menon

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Molecular Cell
|July 17, 2012
PubMed

Insights

Researchers identified TBC1D7 as a core subunit of the tuberous sclerosis complex (TSC) 1-2 complex. This TSC-TBC complex regulates cell growth by inhibiting mTORC1 signaling, crucial for cellular response to poor growth conditions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The tuberous sclerosis complex (TSC) 1-2 protein complex is a critical regulator of cell growth.
  • This complex functions by inhibiting the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway via GTPase-activating protein (GAP) activity towards Rheb.
  • Dysregulation of TSC/mTORC1 signaling is implicated in various cellular disorders.

Purpose of the Study:

  • To identify and characterize novel subunits of the TSC1-TSC2 complex.
  • To elucidate the functional role of TBC1D7 within the TSC complex.
  • To investigate the impact of TBC1D7 on mTORC1 signaling and cellular growth.

Main Methods:

  • Biochemical characterization of protein complexes.
  • In vitro GTPase-activating protein (GAP) assays.
  • TBC1D7 knockdown experiments using RNA interference.
  • Immunofluorescence microscopy to assess protein localization.
  • Analysis of mTORC1 signaling pathway components and autophagy induction.

Main Results:

  • TBC1D7 was identified as a stable and ubiquitous third core subunit of the TSC1-TSC2 complex, forming the functional TSC-TBC complex.
  • The TSC-TBC complex exhibits Rheb-GAP activity, essential for sensing cellular growth conditions.
  • TBC1D7 knockdown disrupted TSC1-TSC2 association, reduced Rheb-GAP activity, and led to increased mTORC1 signaling, delayed autophagy, and enhanced cell growth under nutrient-deprived conditions.
  • TBC1D7 knockdown did not affect TSC2 lysosomal localization.

Conclusions:

  • TBC1D7 is an integral component of the functional TSC complex, mediating its Rheb-GAP activity.
  • The TSC-TBC complex plays a vital role in regulating cell growth and autophagy in response to nutrient availability.
  • TBC1D7 is unlikely to be the TSC3 gene, based on sequencing analyses of TSC patient samples.

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