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A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS

Jiangwei Zhang1, Jinhee Kim, Angela Alexander

  • 11] Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA [2].

Nature Cell Biology
|August 20, 2013
PubMed

Insights

The tuberous sclerosis complex (TSC) protein group localizes to peroxisomes, regulating mTORC1 signaling in response to reactive oxygen species (ROS). This peroxisomal localization is crucial for proper cellular function and mTORC1 suppression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Subcellular localization is increasingly recognized as a key factor in regulating the mechanistic target of rapamycin complex 1 (mTORC1) pathway.
  • The tuberous sclerosis complex (TSC) is a critical signaling node involved in cell growth and metabolism.

Purpose of the Study:

  • To investigate the subcellular localization of the TSC signaling node (TSC1, TSC2, and Rheb).
  • To determine the role of peroxisomal localization of TSC in mTORC1 regulation, particularly in response to reactive oxygen species (ROS).

Main Methods:

  • Immunofluorescence microscopy to determine subcellular localization of TSC proteins.
  • Co-immunoprecipitation assays to identify binding partners (PEX19, PEX5).
  • GTPase-activating protein (GAP) assays to assess Rheb activity.
  • Analysis of mTORC1 signaling and autophagy induction.
  • Studies using cells lacking peroxisomes and TSC2 mutants with impaired peroxisome localization.

Main Results:

  • The TSC signaling node (TSC1, TSC2, Rheb) was found to localize to peroxisomes.
  • Peroxisome-localized TSC proteins interacted with PEX19 and PEX5.
  • Peroxisomal TSC functioned as a Rheb GTPase-activating protein (GAP), suppressing mTORC1 and inducing autophagy.
  • Pathogenic TSC2 mutations disrupted PEX5 binding, peroxisome localization, Rheb GAP activity, and ROS-mediated mTORC1 suppression.
  • Cells lacking peroxisomes showed impaired mTORC1 repression by ROS.
  • TSC2 mutants deficient in peroxisome localization caused neuronal polarity defects and multiple axon formation.

Conclusions:

  • The peroxisome serves as a signaling organelle for mTORC1 regulation.
  • The TSC signaling node plays a critical role in responding to ROS at the peroxisome.
  • Proper peroxisomal localization of TSC is essential for suppressing mTORC1, inducing autophagy, and maintaining neuronal polarity.

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