Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells.
Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells.
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DOI：
10.1038/s41467-021-23003-4
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发表时间：
2021-05-11
影响因子：
16.6
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Xing J;Zhang A;Du Y;Fang M;Minze LJ;Liu YJ;Li XC;Zhang Z
先天免疫细胞在针对病毒感染的保护性免疫中是至关重要的，参与感测外来病毒核酸。在这里，我们报告的聚（ADP-核糖）聚合酶9（PARP 9），PARP家族的成员，作为一个非典型的传感器的RNA病毒启动和放大I型干扰素（IFN）的生产。我们发现在人或小鼠树突状细胞和巨噬细胞中敲低或缺失PARP 9抑制I型IFN的产生以响应双链RNA刺激或RNA病毒感染。此外，由于I型IFN产生受损，PARP 9缺陷的小鼠显示对RNA病毒感染的易感性增强。从机制上讲，我们表明PARP 9识别并结合病毒RNA，导致磷酸肌醇3-激酶（PI 3 K）和AKT 3途径的募集和激活，不依赖于线粒体抗病毒信号传导（MAVS）。然后，PI 3 K/AKT 3通过在Ser 385处磷酸化IRF 3和在Ser 437/438处磷酸化IRF 7来激活IRF 3和IRF 7，介导I型IFN产生。总之，我们揭示了PARP 9作为非经典RNA传感器的关键作用，其依赖于PI 3 K/AKT 3途径来产生I型IFN。这些发现可能对通过靶向PARP 9控制病毒感染和病毒诱导的疾病具有重要的临床意义。天然免疫细胞通过表达一系列核酸传感器在巡逻和检测病毒感染中发挥关键作用。在这里，作者暗示PARP 9参与病毒RNA的检测和通过PI 3 K/AKT 3诱导IFN途径。
Innate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9. Innate immune cells play critical roles patrolling for and detecting viral infection by expression of a range of nucleic acid sensors. Here the authors implicate PARP9 in the detection of viral RNA and the induction of the IFN pathway via PI3K/AKT3.
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