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TRAF4-Mediated LAMTOR1 Ubiquitination Promotes mTORC1 Activation and Inhibits the Inflammation-Induced Colorectal

Linlin Zhao1, Ni Gao1, Xiaoping Peng1

  • 1Tongji University Cancer Center, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, 200092, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 16, 2024
PubMed

Insights

TRAF4-mediated ubiquitination of LAMTOR1 is crucial for mechanistic target of rapamycin complex 1 (mTORC1) activation. This finding reveals a new regulatory mechanism for mTORC1 signaling and offers potential therapeutic targets for related diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism.
  • mTORC1 activation depends on its lysosomal tethering by the Ragulator-Rag complex.
  • The regulation of Ragulator-Rag GTPase interaction is not fully understood.

Purpose of the Study:

  • To investigate the dynamic regulation of the Ragulator complex.
  • To identify the molecular mechanisms controlling mTORC1 activation by amino acid abundance.
  • To explore the role of LAMTOR1 ubiquitination in mTORC1 signaling.

Main Methods:

  • Investigated LAMTOR1 ubiquitination status under varying amino acid conditions.
  • Identified TRAF4 as an E3 ligase interacting with LAMTOR1.
  • Utilized K63-linked polyubiquitination assays and knock-in/knock-out models.
  • Assessed the impact of LAMTOR1 ubiquitination on Rag GTPase binding and mTORC1 activity.
  • Examined the role of TRAF4 and LAMTOR1 ubiquitination in inflammation-induced colon cancer models.

Main Results:

  • LAMTOR1, a Ragulator component, undergoes dynamic ubiquitination dependent on amino acid levels.
  • TRAF4 directly interacts with LAMTOR1 and catalyzes its K63-linked polyubiquitination at K151.
  • TRAF4-mediated LAMTOR1 ubiquitination enhances its binding to Rag GTPases, promoting mTORC1 activation.
  • Disruption of LAMTOR1 ubiquitination (K151R mutation) or TRAF4 knockout inhibits amino acid-induced mTORC1 activation.
  • Blocking this pathway accelerates inflammation-induced colon cancer development.

Conclusions:

  • TRAF4-mediated LAMTOR1 ubiquitination is a key regulatory mechanism for mTORC1 activation.
  • This ubiquitination event is essential for integrating amino acid signals to control mTORC1.
  • The TRAF4-LAMTOR1 axis represents a potential therapeutic target for diseases driven by mTORC1 dysregulation, including colon cancer.
Keywords:
LAMTOR1Rag GTPaseTRAF4mTORC1ubiquitination

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