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Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1

Yanghao Zhong1,2,3, Ayse Z Sahan1,2,4, Zhengyao Shao1

  • 1Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.

Nature Chemical Biology
|May 14, 2026
PubMed

Insights

Mechanistic target of rapamycin complex 1 (mTORC1) signaling is compartmentalized. A new tool, TerminaTOR, reveals mTORC1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) is a key nutrient sensor regulating protein translation and cell growth.
  • While traditionally localized to the lysosome, mTORC1 signaling is now known to occur at various subcellular locations, including the nucleus.
  • The specific functions and compartmentalization of mTORC1 signaling at these distinct locations remain largely unknown.

Purpose of the Study:

  • To investigate the subcellular functions of mTORC1.
  • To develop a tool for interrogating spatially distinct mTORC1 signaling pools.
  • To elucidate the roles of nuclear mTORC1 in gene regulation.

Main Methods:

  • Development of TerminaTOR, a genetically encodable, location-specific mTORC1 inhibitor.
  • Targeting TerminaTOR to lysosomes to study canonical mTORC1 functions and induce autophagy.
  • Targeting TerminaTOR to the nucleus to specifically inhibit nuclear mTORC1 activity.

Main Results:

  • Lysosomal targeting of TerminaTOR successfully inhibited lysosomal mTORC1 and induced autophagy.
  • Nuclear targeting of TerminaTOR specifically inhibited nuclear mTORC1.
  • Nuclear mTORC1 was found to play a noncanonical role in regulating the transcription of CCAAT motif-containing genes.

Conclusions:

  • mTORC1 signaling exhibits functional spatial compartmentalization within the cell.
  • TerminaTOR is a valuable tool for dissecting the spatially regulated functions of mTORC1.
  • Nuclear mTORC1 has distinct roles in gene transcription, separate from its lysosomal functions.

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