Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5′-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host triphosphate RNA packaged in extracellular vesicles and induces enhanced RIG-I activation in cells exposed to extracellular vesicles. Virus infection of cells lacking DUSP11 results in a higher proportion of triphosphorylated viral transcripts and attenuated virus replication, which is rescued by reducing RIG-I expression. Consistent with the activity of DUSP11 in the cellular RIG-I response, mice lacking DUSP11 display lower viral loads, greater sensitivity to triphosphorylated RNA, and a signature of enhanced interferon activity in select tissues. Our results reveal the importance of controlling 5′-triphosphate RNA levels to prevent aberrant RIG-I signaling and demonstrate DUSP11 as a key effector of this mechanism.

中文翻译：

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DUSP11介导的5'-三磷酸RNA调控调节RIG-I敏感性

阐明调节病原体识别受体敏感性的机制对于理解感染和炎症至关重要。在这里，我们证明RNA三磷酸酶双特异性磷酸酶11（DUSP11）对宿主和病毒来源的5'-三磷酸RNA均起作用，从而使其在诱导RIG-I介导的免疫反应中的活性降低。降低DUSP11水平会改变包装在细胞外囊泡中的宿主三磷酸RNA，并在暴露于细胞外囊泡的细胞中诱导增强的RIG-I激活。缺少DUSP11的细胞被病毒感染会导致更高比例的三磷酸化病毒转录物和减弱的病毒复制，这可以通过减少RIG-I表达来挽救。与DUSP11在细胞RIG-I反应中的活性一致，缺乏DUSP11的小鼠显示出较低的病毒载量，对三磷酸化RNA的敏感性更高，并且在选定的组织中具有增强的干扰素活性的标志。我们的结果揭示了控制5'-三磷酸RNA水平以防止异常RIG-I信号传导的重要性，并证明DUSP11是该机制的关键效应子。