Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2020 Sep 4;9:e57837. doi: 10.7554/eLife.57837.
Reactive oxygen species (ROS) are by-products of cellular respiration that can promote oxidative stress and damage cellular proteins and lipids. One canonical role of ROS is to defend the cell against invading bacterial and viral pathogens. Curiously, some viruses, including herpesviruses, thrive despite the induction of ROS, suggesting that ROS are beneficial for the virus. However, the underlying mechanisms remain unclear. Here, we found that ROS impaired interferon response during murine herpesvirus infection and that the inhibition occurred downstream of cytoplasmic DNA sensing. We further demonstrated that ROS suppressed the type I interferon response by oxidizing Cysteine 147 on murine stimulator of interferon genes (STING), an ER-associated protein that mediates interferon response after cytoplasmic DNA sensing. This inhibited STING polymerization and activation of downstream signaling events. These data indicate that redox regulation of Cysteine 147 of mouse STING, which is equivalent to Cysteine 148 of human STING, controls interferon production. Together, our findings reveal that ROS orchestrates anti-viral immune responses, which can be exploited by viruses to evade cellular defenses.
活性氧 (ROS) 是细胞呼吸的副产物，可促进氧化应激并损害细胞蛋白质和脂质。ROS 的一个典型作用是抵抗入侵的细菌和病毒病原体。奇怪的是，一些病毒，包括疱疹病毒，尽管诱导了 ROS，但仍能茁壮成长，这表明 ROS 对病毒有益。然而，潜在的机制尚不清楚。在这里，我们发现在小鼠疱疹病毒感染过程中，ROS 损害了干扰素反应，并且这种抑制发生在细胞质 DNA 感应的下游。我们进一步证明，ROS 通过氧化 ER 相关蛋白干扰素基因刺激物 (STING) 上的半胱氨酸 147 来抑制 I 型干扰素反应，该蛋白在细胞质 DNA 感应后介导干扰素反应。这抑制了 STING 聚合和下游信号事件的激活。这些数据表明，半胱氨酸 147 的氧化还原调节，相当于人类 STING 上的半胱氨酸 148，控制干扰素的产生。总之，我们的研究结果表明，ROS 协调抗病毒免疫反应，而病毒可以利用这些反应来逃避细胞防御。
