Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake
Songhua Hu, Xiadi He, Ji Nie, Jun‐Li Hou, Jiang Wu, Xiaoyan Liu, Yun Wei, Huiru Tang, Wen-Xing Sun, Shu-Xian Zhou, Yiyuan Yuan, Yanpeng An, Guoquan Yan, Yan Lin, Pengcheng Lin, Jean J. Zhao, Mingliang Ye, Jian‐Yuan Zhao, Wei Xu, Shimin Zhao
Abstract
Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.