Glycogen Synthase Kinase 3β Regulates IRF3 Transcription Factor-Mediated Antiviral Response via Activation of the Kinase TBK1
Glycogen Synthase Kinase 3β Regulates IRF3 Transcription Factor-Mediated Antiviral Response via Activation of the Kinase TBK1
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DOI：
10.1016/j.immuni.2010.11.021
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发表时间：
2010-12-22
期刊：
影响因子：
32.4
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Lei, Cao-Qi;Zhong, Bo;Shu, Hong-Bing
病毒感染激活转录因子IRF3和核因子-kappaB，它们协同诱生I型干扰素(IFN)。在这里，我们发现糖原合成酶激酶3β(GSK3β)是病毒触发的IRF3和NF-kappa B激活、干扰素-β诱导和细胞抗病毒反应的重要调节因子。GSK3β的过表达增强了病毒诱导的IRF3的激活和IFNB1基因的转录，而GSK3β的表达减少或缺失则削弱了病毒诱导的IRF3和NF-kappa B的激活、IFNB1基因的转录以及细胞抗病毒反应。GSK3β以病毒感染依赖的方式与激酶TBK1物理关联。GSK3β促进了病毒诱导的IRF3激活和干扰素-β诱导的病毒诱导的IRF3激活和干扰素-β的诱导。GSK3β在病毒诱导的信号转导中的作用不依赖于它的激酶活性。我们的发现表明，GSK3β通过促进TBK1的激活在病毒触发的IRF3激活中发挥重要作用，并为细胞抗病毒反应的分子机制提供了新的见解。
Viral infection activates transcription factors IRF3 and NF-kappa B, which collaborate to induce type I interferons (IFNs). Here, we identified glycogen synthase kinase 3 beta (GSK3 beta) as an important regulator for virus-triggered IRF3 and NF-kappa B activation, IFN-beta induction, and cellular antiviral response. Overexpression of GSK3 beta potentiated virus-induced activation of IRF3 and transcription of the IFNB1 gene, whereas reduced expression or deletion of GSK3 beta impaired virus-induced IRF3 and NF-kappa B activation, transcription of the IFNB1 gene, as well as cellular antiviral response. GSK3 beta physically associated with the kinase TBK1 in a viral infection-dependent manner. GSK3 beta promoted TBK1 self-association and autophosphorylation at Ser172, which is critical for virus-induced IRF3 activation and IFN-beta induction. The effect of GSK3 beta on virus-induced signaling is independent of its kinase activity. Our findings suggest that GSK3 beta plays important roles in virus-triggered IRF3 activation by promoting TBK1 activation and provide new insights to the molecular mechanisms of cellular antiviral response.