Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration
Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration
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Rab5a 激活 IRS1 以协调肌肉再生过程中的 IGF-AKT-mTOR 信号传导和成肌细胞分化
DOI：
10.1038/s41418-020-0508-1
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发表时间：
2020-02-12
影响因子：
12.4
通讯作者：
Zhou, Yi Ting
中科院分区：
文献类型：
--
作者：
Cong, Xiao Xia;Gao, Xiu Kui;Zhou, Yi Ting
Rab 5是核内体生物发生和转运的主要调节因子，但其在体内的生理功能仍不清楚。在这里，我们发现Rab 5a在几种体内和体外肌生成模型中上调。通过产生肌原性Rab 5a缺陷小鼠，我们揭示了Rab 5a在调节骨骼肌再生中的重要作用。我们进一步揭示Rab 5a促进成肌细胞分化，并直接与胰岛素受体底物1（IRS 1）相互作用，IRS 1是IGF信号传导的重要支架蛋白。Rab 5a以GTP依赖的方式与IRS 1相互作用，并且这种相互作用在IGF-1活化和肌源性分化后增强。我们随后确定，IRS 1的精氨酸207和222和Rab 5a的酪氨酸82，89和90是介导该协会的关键氨基酸残基。从机制上讲，Rab 5a通过协调IRS 1和IGF受体（IGFR）之间的结合并调节IRS 1的细胞内膜靶向来调节IRS 1的活化。成肌诱导的和IGF诱发的AKT-mTOR信号传导都依赖于Rab 5a。Rab 5a的肌源性缺失也减少了骨骼肌再生期间AKT-mTOR信号传导的激活。总之，我们的研究揭示了Rab 5a在调节肌肉再生中的生理功能，并描绘了Rab 5a作为通过激活IRS 1控制AKT-mTOR信号传导的关键开关的新作用。
Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.