Novel effects of Brefeldin A (BFA) in signaling through the insulin receptor (IR) pathway and regulating FoxO1-mediated transcription.
Novel effects of Brefeldin A (BFA) in signaling through the insulin receptor (IR) pathway and regulating FoxO1-mediated transcription.
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DOI：
10.4161/cl.27732
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Sztul E
中科院分区：
文献类型：
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作者：
Wyrozumska P;Ashley JW;Ramanadham S;Liu Q;Garvey WT;Sztul E
布雷菲德菌素A（BFA）是一种真菌代谢产物，最出名的是其能够抑制ADP核糖基化因子（Arf）的激活，从而抑制分泌流量。BFA似乎还通过诱导GLUT 4葡萄糖转运蛋白从细胞内储存转移到细胞表面来调节其运输。GLUT 4的这种再分布通常由胰岛素介导的信号传导调节。因此，我们测试了BFA是否可能与胰岛素途径相交。我们报告说，BFA导致胰岛素受体（IR），IRS-1，Akt-2和AS 160的胰岛素途径的组件的激活。该反应通过磷酸肌醇-3-激酶（PI 3 K）和Akt激酶介导，因为PI 3 K抑制剂渥曼青霉素和Akt抑制剂MK 2206和哌立福新抑制BFA作用。BFA介导的胰岛素途径活化导致Akt介导的胰岛素应答转录因子FoxO 1磷酸化。这导致FoxO 1的核排斥和胰岛素应答基因SIRT-1的转录减少。我们的研究结果表明BFA在信号传导和转录中具有新的作用，并暗示BFA具有多个细胞内靶点，可用于调节包括囊泡运输、信号传导和转录在内的多种细胞反应。
Brefeldin A (BFA) is a fungal metabolite best known for its ability to inhibit activation of ADP-ribosylation factor (Arf) and thereby inhibit secretory traffic. BFA also appears to regulate the trafficking of the GLUT4 glucose transporter by inducing its relocation from intracellular stores to the cell surface. Such redistribution of GLUT4 is normally regulated by insulin-mediated signaling. Hence, we tested whether BFA may intersect with the insulin pathway. We report that BFA causes the activation of the insulin receptor (IR), IRS-1, Akt-2, and AS160 components of the insulin pathway. The response is mediated through phosphoinositol-3-kinase (PI3K) and Akt kinase since the PI3K inhibitor wortmannin and the Akt inhibitors MK2206 and perifosine inhibit the BFA effect. BFA-mediated activation of the insulin pathway results in Akt-mediated phosphorylation of the insulin-responsive transcription factor FoxO1. This leads to nuclear exclusion of FoxO1 and a decrease in transcription of the insulin-responsive gene SIRT-1. Our findings suggest novel effects for BFA in signaling and transcription, and imply that BFA has multiple intracellular targets and can be used to regulate diverse cellular responses that include vesicular trafficking, signaling and transcription.