College of Life Sciences, Wuhan University, Wuhan 430072, China.
Immunity. 2010 Dec 14;33(6):878-89. doi: 10.1016/j.immuni.2010.11.021. Epub 2010 Dec 9.
Viral infection activates transcription factors IRF3 and NF-κB, which collaborate to induce type I interferons (IFNs). Here, we identified glycogen synthase kinase 3β (GSK3β) as an important regulator for virus-triggered IRF3 and NF-κB activation, IFN-β induction, and cellular antiviral response. Overexpression of GSK3β potentiated virus-induced activation of IRF3 and transcription of the IFNB1 gene, whereas reduced expression or deletion of GSK3β impaired virus-induced IRF3 and NF-κB activation, transcription of the IFNB1 gene, as well as cellular antiviral response. GSK3β physically associated with the kinase TBK1 in a viral infection-dependent manner. GSK3β promoted TBK1 self-association and autophosphorylation at Ser172, which is critical for virus-induced IRF3 activation and IFN-β induction. The effect of GSK3β on virus-induced signaling is independent of its kinase activity. Our findings suggest that GSK3β plays important roles in virus-triggered IRF3 activation by promoting TBK1 activation and provide new insights to the molecular mechanisms of cellular antiviral response.
病毒感染激活转录因子 IRF3 和 NF-κB，它们协同诱导 I 型干扰素（IFN）。在这里，我们确定糖原合成酶激酶 3β（GSK3β）是病毒触发的 IRF3 和 NF-κB 激活、IFN-β诱导和细胞抗病毒反应的重要调节剂。GSK3β 的过表达增强了病毒诱导的 IRF3 激活和 IFNB1 基因的转录，而 GSK3β 的表达减少或缺失则损害了病毒诱导的 IRF3 和 NF-κB 激活、IFNB1 基因的转录以及细胞抗病毒反应。GSK3β 以病毒感染依赖性的方式与激酶 TBK1 发生物理关联。GSK3β 促进 TBK1 自身缔合和 Ser172 的自磷酸化，这对于病毒诱导的 IRF3 激活和 IFN-β 诱导至关重要。GSK3β 对病毒诱导信号的影响与其激酶活性无关。我们的研究结果表明，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。
