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Tryptophanylation of insulin receptor by WARS attenuates insulin signaling
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. © 2024, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Authors : Sun W.-X.; Zhang K.-H.; Zhou Q.; Hu S.-H.; Lin Y.; Xu W.; Zhao S.-M.; Yuan Y.-Y.
Source : Springer Science and Business Media Deutschland GmbH
Article Information
| Year | 2024 |
| Type | Article |
| DOI | 10.1007/s00018-023-05082-2 |
| ISSN | 1420682X |
| Volume | 81 |
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