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

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.