Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.
Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.
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胰岛素受体底物 1 的相分离驱动胰岛素/IGF-1 信号体的形成
DOI：
10.1038/s41421-022-00426-x
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发表时间：
2022-06-28
期刊：
影响因子：
33.5
通讯作者：
Zhou, Yi Ting
中科院分区：
文献类型：
--
作者：
Gao, Xiu Kui;Rao, Xi Sheng;Cong, Xiao Xia;Sheng, Zu Kang;Sun, Yu Ting;Xu, Shui Bo;Wang, Jian Feng;Liang, Yong Heng;Lu, Lin Rong;Ouyang, Hongwei;Ge, Huiqing;Guo, Jian-sheng;Wu, Hang-jun;Sun, Qi Ming;Wu, Hao-bo;Bao, Zhang;Zheng, Li Ling;Zhou, Yi Ting
胰岛素受体底物1（insulin receptor substrate 1，IRS-1）作为胰岛素/IGF信号传导的关键节点，在代谢调节中起着重要作用。IRS-1的长且非结构化的C末端区域募集下游效应物以促进胰岛素/IGF信号。然而，其潜在的分子基础仍然难以捉摸。在这里，我们发现IRS-1的C-末端经历液-液相分离（LLPS）。静电和疏水相互作用被认为是驱动IRS-1 LLPS。IRS-1的自缔合主要由301-600区域介导，驱动IRS-1 LLPS形成胰岛素/IGF-1信号体。此外，YXXM基序的酪氨酸残基，招募下游效应器，也有助于IRS-1的自缔合和LLPS。IRS-1 LLPS的损伤减弱了其对胰岛素/IGF-1信号传导的积极作用。代谢性疾病相关的G972 R突变损害IRS-1的自缔合和LLPS。我们的研究结果描绘了IRS-1介导的信号体的LLPS作为胰岛素/IGF-1信号传导的组织中心的机制，并暗示了异常IRS-1 LLPS在代谢疾病中的作用。
As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.
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