Zhou Kun, Chen Qiaoli, Chen Jiamou, Liang Derong, Feng Weikuan, Liu Minjun, Wang Qi, Wang Ruizhen, Ouyang Qian, Quan Chao, Chen Shuai
MOE Key Laboratory of Model Animal for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
Cell Discov. 2022 Jul 5;8(1):64. doi: 10.1038/s41421-022-00430-1.
Insulin signals through its receptor to recruit insulin receptor substrates (IRS) and phosphatidylinositol 3-kinase (PI3K) to the plasma membrane for production of phosphatidylinositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], which consequently activates protein kinase B (PKB). How insulin signals transduce from the plasma membrane into the cytoplasm is not clearly understood. Here we show that liquid-liquid phase separation (LLPS) plays a critical role in spatiotemporal control of insulin signaling through regulating multiple components including IRS1. Both protein concentration and insulin stimulation can drive the formation of intracellular IRS1 condensates through LLPS. Components including PI(4,5)P2, p85-PI3K and PDK1 are constitutively present in IRS1 condensates whereas production of PIP3 and recruitment of PKB in them are induced by insulin. Thus, IRS1 condensates function as intracellular signal hubs to mediate insulin signaling, whose formation is impaired in insulin resistant cells. Collectively, these data reveal an important function of LLPS in spatiotemporal control of insulin signaling.
胰岛素通过其受体发出信号，招募胰岛素受体底物（IRS）和磷脂酰肌醇3激酶（PI3K）至质膜，从而将磷脂酰肌醇-4,5-二磷酸[PI(4,5)P2]转化为磷脂酰肌醇-3,4,5-三磷酸（PIP3），进而激活蛋白激酶B（PKB）。目前尚不清楚胰岛素信号是如何从质膜传导至细胞质的。在此，我们表明液-液相分离（LLPS）通过调节包括IRS1在内的多种组分，在胰岛素信号的时空控制中发挥关键作用。蛋白质浓度和胰岛素刺激均可通过LLPS驱动细胞内IRS1凝聚物的形成。包括PI(4,5)P2、p85-PI3K和PDK1在内的组分在IRS1凝聚物中持续存在，而其中PIP3的产生和PKB的招募则由胰岛素诱导。因此，IRS1凝聚物作为细胞内信号枢纽介导胰岛素信号传导，其形成在胰岛素抵抗细胞中受损。总体而言，这些数据揭示了LLPS在胰岛素信号时空控制中的重要功能。
