Spatiotemporal regulation of insulin signaling by liquid-liquid phase separation.

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）到质膜，以便从磷脂酰肌醇 - 4,5 - 二磷酸[PI(4,5)P2]产生磷脂酰肌醇 - 3,4,5 - 三磷酸（PIP3），进而激活蛋白激酶B（PKB）。胰岛素信号如何从质膜转导到细胞质尚不清楚。在此我们表明，液 - 液相分离（LLPS）通过调节包括IRS1在内的多种成分，在胰岛素信号的时空控制中起着关键作用。蛋白质浓度和胰岛素刺激都可通过LLPS驱动细胞内IRS1凝聚物的形成。包括PI(4,5)P2、p85 - PI3K和PDK1在内的成分在IRS1凝聚物中组成性存在，而其中PIP3的产生和PKB的招募是由胰岛素诱导的。因此，IRS1凝聚物作为细胞内信号枢纽介导胰岛素信号，其形成在胰岛素抵抗细胞中受损。总之，这些数据揭示了LLPS在胰岛素信号时空控制中的重要作用。