1. Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.
- Author
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Sun, Wen-Xing, Zhang, Kai-Hui, Zhou, Qian, Hu, Song-Hua, Lin, Yan, Xu, Wei, Zhao, Shi-Min, and Yuan, Yi-Yuan
- Abstract
Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW−K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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