Abstract
Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.
Highlights
Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 pathway
Since LRS can influence protein synthesis via its activity in the mammalian target of rapamycin complex 1 (mTORC1) pathway or tRNA charging, we investigated whether the two activities could be decoupled
Our results provide validation that LRS has a crucial role as a leucine sensor for mTORC1 activation
Summary
Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. We selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity It effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. 3 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, South Korea. Sensing of intracellular amino acid availability is mediated by mammalian target of rapamycin complex 1 (mTORC1), which controls many cellular processes such as protein synthesis, autophagy, and cell growth, and is implicated in human diseases including cancer, obesity, diabetes, and neurodegeneration[2,3,4,5]. The selected compound BC-LI-0186 efficiently inhibited leucinedependent mTORC1 activity and the growth of cancer cells that express drug-resistant MTOR mutations
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