Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.
During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
在病毒感染过程中，衔接蛋白 MAVS 和 STING 分别从细胞质核酸传感器 RIG-I 和 cGAS 转导信号，诱导 I 型干扰素（IFNs）和其他抗病毒分子。在这里，我们表明 MAVS 和 STING 具有两个保守的丝氨酸和苏氨酸簇，这些簇可被激酶 IKK 和/或 TBK1 磷酸化，以响应刺激。磷酸化的 MAVS 和 STING 然后与干扰素调节因子 3（IRF3）的正电荷表面结合，从而招募 IRF3 使其通过 TBK1 磷酸化和激活。我们还表明，Toll 样受体信号转导中的衔接蛋白 TRIF 通过类似的依赖于磷酸化的机制激活 IRF3。这些结果表明，先天衔接蛋白的磷酸化是一种选择性招募 IRF3 以激活 I 型 IFN 途径的重要且保守的机制。
