Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Medical Epigenetics, and Children's Hospital of Fudan University, Shanghai 200438, P.R. China.
Department of Chemistry, Fudan University, Shanghai 200438, P.R. China.
Cell Rep. 2022 Mar 15;38(11):110509. doi: 10.1016/j.celrep.2022.110509.
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.
蛋白质脂肪酸酰化调节许多细胞信号通路。多不饱和脂肪酸（PUFA）发挥着多种生理作用，包括细胞信号调节，但其潜在机制尚待充分理解。在此，我们报告二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）通过修饰 PDK1 和 AKT2 来调节 PI3K-AKT 信号通路。给予 DHA 的小鼠表现出信号通路中蛋白质磷酸化的改变。含亚甲基桥的 DHA/EPA 通过自由基途径将色氨酸 448/543 上的 δ1 碳原子酰化到 PDK1 中，以及将色氨酸 414 酰化到 AKT2 中，将这两种蛋白募集到细胞质膜，并以色氨酸酰化依赖但胰岛素非依赖的方式在培养细胞和小鼠中激活 PI3K 信号通路和葡萄糖摄取。DHA/EPA 耗尽细胞质 PDK1 和 AKT2 并诱导胰岛素抵抗。在小鼠中敲除 Akt2 可消除 DHA/EPA 诱导的 PI3K-AKT 信号通路。我们的研究结果确定了 PUFA 的亚甲基桥色氨酸酰化，这是一种调节细胞信号的蛋白质脂肪酸酰化，可能是含亚甲基桥的 PUFAs 的多种作用的基础。
