2. Academic Validation
  3. RNF126 suppresses amino acid-mediated mTORC1 signaling pathway by ubiquitinating ILF3 in HEK293T cells

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

  • Cell Signal. 2025 Sep 2:112110. doi: 10.1016/j.cellsig.2025.112110.
Bin Hu 1,  Meng-Di Shang 2,  Xi Wang 3,  Xiao-Gang Zhang 4,  Meng-Hua Dong 3,  Qi Cao 3,  Xiao-Dan Wei 3,  Yan-Chun Han 3,  Fan Li 3,  Zhen-Lin Yang 5,  Lu-Ying Liu 6,  Jiu-Qiang Wang 7
Affiliations

Affiliations

  • 1 The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong 256603, PR China.
  • 2 Peninsular Cancer Center, Binzhou Medical University, Yantai, Shandong 264003, PR China.
  • 3 School of Basic Medical, Binzhou Medical University, Yantai, Shandong 264003, PR China.
  • 4 School of Special Education and Rehabilitation, Binzhou Medical University, Yantai 264003, PR China.
  • 5 The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong 256603, PR China. Electronic address: yzhlin@126.com.
  • 6 School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266001, PR China. Electronic address: llixq@126.com.
  • 7 School of Basic Medical, Binzhou Medical University, Yantai, Shandong 264003, PR China. Electronic address: wangjiuqiang1007@bzmc.edu.cn.
PMID: 40907628 DOI: 10.1016/j.cellsig.2025.112110
Abstract

The mammalian Target of Rapamycin Complex 1 (mTORC1) serves as a metabolic hub that integrates external nutrients to promote cell growth and metabolism, with its activation closely associated with accelerated Cancer progression. Interleukin enhancer-binding factor 3 (ILF3) has been identified as a negative regulator of mTORC1 by tethering GATOR1/2 to the lysosomal membrane during amino acid sensing. However, the regulatory mechanisms of the ILF3-mediated mTORC1 signaling pathway remain unclear. In this study, we demonstrate that RNF126 negatively regulates mTORC1 signaling by promoting the K63-linked ubiquitination of ILF3 in HEK293T cells. Silencing RNF126 significantly attenuated the interaction between ILF3 and the GATOR2 complex. Notably, RNF126 depletion in MCF7 cells suppressed breast Cancer progression in preclinical models, highlighting its potential as a therapeutic target.

Keywords

Amino acid; ILF3; RNF126; mTORC1.

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