Sensing and Transmitting Intracellular Amino Acid Signals through Reversible Lysine Aminoacylations

Publication date: Available online 30 November 2017
Source:Cell Metabolism
Author(s): Xia-Di He, Wei Gong, Jia-Nong Zhang, Ji Nie, Cui-Fang Yao, Fu-Shen Guo, Yan Lin, Xiao-Hui Wu, Feng Li, Jie Li, Wei-Cheng Sun, En-Duo Wang, Yan-Peng An, Hui-Ru Tang, Guo-Quan Yan, Peng-Yuan Yang, Yun Wei, Yun-Zi Mao, Peng-Cheng Lin, Jian-Yuan Zhao, Yanhui Xu, Wei Xu, Shi-Min Zhao
Amino acids are known regulators of cellular signaling and physiology, but how they are sensed intracellularly is not fully understood. Herein, we report that each aminoacyl-tRNA synthetase (ARS) senses its cognate amino acid sufficiency through catalyzing the formation of lysine aminoacylation (K-AA) on its specific substrate proteins. At physiologic levels, amino acids promote ARSs bound to their substrates and form K-AAs on the ɛ-amine of lysines in their substrates by producing reactive aminoacyl adenylates. The K-AA marks can be removed by deacetylases, such as SIRT1 and SIRT3, employing the same mechanism as that involved in deacetylation. These dynamically regulated K-AAs transduce signals of their respective amino acids. Reversible leucylation on ras-related GTP-binding protein A/B regulates activity of the mammalian target of rapamycin complex 1. Glutaminylation on apoptosis signal-regulating kinase 1 suppresses apoptosis. We discovered non-canonical functions of ARSs and revealed systematic and functional amino acid sensing and signal transduction networks.

Graphical abstract

Teaser

He et al. reveal that tRNA synthetases sense sufficiency of amino acids and act as aminoacyl transferases to modify ɛ-amines of lysines in proteins, with leucylation of RagA/B regulating mTORC1 activity and glutaminylation of ASK1 inhibiting apoptosis. Lysine aminoacylation marks are removed by SIRT1 and SIRT3.


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