The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation.
The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation.
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Axin/TNKS 复合物与 KIF3A 相互作用，是胰岛素刺激的 GLUT4 易位所必需的
作者：
葡萄糖转运蛋白GLUT 4对胰岛素刺激的葡萄糖摄取在全身葡萄糖稳态中起着重要作用，其失调导致2型糖尿病。然而，调节胰岛素刺激的葡萄糖摄取的分子组成和机制仍不清楚。在这里，我们证明了Axin与ADP-核糖基化酶端锚聚合酶2（TNKS 2）和驱动蛋白马达蛋白KIF 3A相互作用，形成了一个三元复合物，对胰岛素引起的GLUT 4易位至关重要。特异性敲除复合物的单个组分可减弱胰岛素刺激的GLUT 4向质膜的转运。重要的是，TNKS 2 −/−小鼠在禁食后重新进食时表现出胰岛素敏感性降低和血糖水平升高。从机制上讲，我们证明了在没有胰岛素的情况下，Axin，TNKS和KIF 3A与GLUT 4在trans-Golgi网络上共定位。胰岛素治疗抑制TNKS的ADP-核糖基化酶活性，导致ADP核糖基化和Axin和TNKS的泛素化减少，并同时稳定复合物。抑制Akt（胰岛素信号传导的主要效应激酶）可消除胰岛素介导的复合物稳定性。因此，我们阐明了一种新的蛋白质复合物，直接与胰岛素刺激的GLUT 4易位的马达蛋白驱动蛋白。
Insulin-stimulated glucose uptake by the glucose transporter GLUT4 plays a central role in whole-body glucose homeostasis, dysregulation of which leads to type 2 diabetes. However, the molecular components and mechanisms regulating insulin-stimulated glucose uptake remain largely unclear. Here, we demonstrate that Axin interacts with the ADP-ribosylase tankyrase 2 (TNKS2) and the kinesin motor protein KIF3A, forming a ternary complex crucial for GLUT4 translocation in response to insulin. Specific knockdown of the individual components of the complex attenuated insulin-stimulated GLUT4 translocation to the plasma membrane. Importantly, TNKS2−/− mice exhibit reduced insulin sensitivity and higher blood glucose levels when re-fed after fasting. Mechanistically, we demonstrate that in the absence of insulin, Axin, TNKS and KIF3A are co-localized with GLUT4 on the trans-Golgi network. Insulin treatment suppresses the ADP-ribosylase activity of TNKS, leading to a reduction in ADP ribosylation and ubiquitination of both Axin and TNKS, and a concurrent stabilization of the complex. Inhibition of Akt, the major effector kinase of insulin signaling, abrogates the insulin-mediated complex stabilization. We have thus elucidated a new protein complex that is directly associated with the motor protein kinesin in insulin-stimulated GLUT4 translocation.
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