Tryptophanylation of Insulin Receptor by WARS Attenuates Insulin Signaling

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Jan 11

PMID 38212570

Authors

Wen-Xing Sun

Kai-Hui Zhang

Qian Zhou

Song-Hua Hu

Yan Lin

Wei Xu

Shi-Min Zhao

Yi-Yuan Yuan

Affiliations

Soon will be listed here.

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 IR 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.

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