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RNF126 suppresses amino acid-mediated mTORC1 signaling pathway by ubiquitinating ILF3 in HEK293T cells

Bin Hu1, Meng-Di Shang2, Xi Wang3

  • 1The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong 256603, PR China.

Cellular Signalling
|September 4, 2025
PubMed

Insights

RNF126 negatively regulates the mTORC1 pathway by ubiquinating ILF3. This finding reveals a new mechanism controlling cell growth and offers a potential therapeutic target for breast cancer.

Area of Science:

  • Cellular metabolism
  • Signal transduction pathways
  • Oncology research

Background:

  • Mammalian Target of Rapamycin Complex 1 (mTORC1) is a key metabolic regulator promoting cell growth, and its hyperactivation is linked to cancer progression.
  • Interleukin enhancer-binding factor 3 (ILF3) acts as a negative regulator of mTORC1 by interacting with the GATOR complex during nutrient sensing.
  • The precise regulatory mechanisms governing ILF3's role in mTORC1 signaling are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the ILF3-mediated mTORC1 signaling pathway.
  • To investigate the role of RNF126 in the regulation of ILF3 and mTORC1 signaling.
  • To evaluate the therapeutic potential of targeting this pathway in breast cancer models.

Main Methods:

  • Utilized HEK293T cells to study the interaction between RNF126, ILF3, and the GATOR complex.
  • Performed ubiquitination assays to assess the effect of RNF126 on ILF3.
  • Employed MCF7 breast cancer cells in preclinical models to assess the impact of RNF126 depletion on tumor progression.

Main Results:

  • Demonstrated that RNF126 negatively regulates mTORC1 signaling through K63-linked ubiquitination of ILF3.
  • Showed that RNF126 silencing disrupts the interaction between ILF3 and the GATOR2 complex.
  • Observed that RNF126 depletion suppressed breast cancer progression in preclinical models.

Conclusions:

  • RNF126 acts as a novel negative regulator of mTORC1 signaling by modulating ILF3 ubiquitination and its interaction with the GATOR complex.
  • RNF126 is a potential therapeutic target for inhibiting mTORC1 signaling in breast cancer.
  • Further research into the RNF126-ILF3 axis could reveal new strategies for cancer treatment.
Keywords:
Amino acidILF3RNF126mTORC1

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