Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.
Wen-Xing SunKai-Hui ZhangQian ZhouSong-Hua HuYan LinWei XuShi-Min ZhaoYi-Yuan YuanPublished in: Cellular and molecular life sciences : CMLS (2024)
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 IR W-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.
Keyphrases
- type diabetes
- insulin resistance
- glycemic control
- adipose tissue
- high fat diet induced
- metabolic syndrome
- amino acid
- end stage renal disease
- blood glucose
- signaling pathway
- polycystic ovary syndrome
- newly diagnosed
- skeletal muscle
- blood pressure
- machine learning
- cell proliferation
- peritoneal dialysis
- drug induced
- prognostic factors
- deep learning
- physical activity
- big data
- body mass index
- endothelial cells
- patient reported