Spatiotemporal regulation of insulin signaling by liquid-liquid phase separation

Kun Zhou; Qiaoli Chen; Jiamou Chen; Derong Liang; Weikuan Feng; Minjun Liu; Qi Wang; Ruizhen Wang; Qian Ouyang; Chao Quan; Shuai Chen

doi:10.1038/s41421-022-00430-1

Spatiotemporal regulation of insulin signaling by liquid-liquid phase separation

Cell Discov. 2022 Jul 5;8(1):64. doi: 10.1038/s41421-022-00430-1.

Authors

Kun Zhou^#^{1

2}, Qiaoli Chen^#^{1

2}, Jiamou Chen¹, Derong Liang¹, Weikuan Feng¹, Minjun Liu¹, Qi Wang¹, Ruizhen Wang¹, Qian Ouyang¹, Chao Quan^{3

4}, Shuai Chen^{5

6}

Affiliations

¹ 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.
² Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
³ 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. quanchao@nicemice.cn.
⁴ Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu, China. quanchao@nicemice.cn.
⁵ 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. schen6@163.com.
⁶ Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu, China. schen6@163.com.

^# Contributed equally.

Abstract

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.