RIG-I-like receptors (RLRs)-mitochondrial antiviral signaling protein (MAVS) are crucial for type I interferon (IFN) signaling pathway and innate immune responses triggered by RNA viruses. However, the regulatory molecular mechanisms underlying RNA virus-activated type I IFN signaling pathway remain incompletely understood. Here, we found that protein arginine methyltransferase 7 (PRMT7) serves as a negative regulator of the type I IFN signaling pathway by interacting with MAVS and catalyzing monomethylation of arginine 232 (R232me1) in MAVS. RNA virus infection leads to the downregulation and dissociation of PRMT7 from MAVS as well as the decrease of R232me1 methylation, enhancing MAVS/RIG-I interaction, MAVS aggregation, type I IFN signaling activation, and antiviral immune responses. Knock-in mice with MAVS R232 substituted with lysine ( Mavs R232K -KI) are more resistant to Vesicular Stomatitis Virus infection due to enhanced antiviral immune responses. PiPRMT7-MAVS, a short peptide inhibitor designed to interrupt the interaction between PRMT7 and MAVS, inhibits R232me1 methylation, thereby enhancing MAVS/RIG-I interaction, promoting MAVS aggregation, activating type I IFN signaling, and bolstering antiviral immune responses to suppress RNA virus replication. Moreover, the clinical relevance of PRMT7 is highlighted that it is significantly downregulated in RNA virus-infected clinical samples, such as blood samples from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus, as well as H1N1-infected bronchial epithelial cells. Our findings uncovered that PRMT7-mediated arginine methylation plays critical roles in regulating MAVS-mediated antiviral innate immune responses, and targeting arginine methylation might represent a therapeutic avenue for treating RNA viral infection.

中文翻译：

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靶向 PRMT7 介导的 MAVS 单甲基化可增强抗病毒先天免疫反应并抑制 RNA 病毒复制


RIG-I 样受体 （RLR）-线粒体抗病毒信号转导蛋白 （MAVS） 对 I 型干扰素 （IFN） 信号通路和 RNA 病毒触发的先天免疫反应至关重要。然而，RNA 病毒激活的 I 型 IFN 信号通路的调节分子机制仍不完全清楚。在这里，我们发现蛋白精氨酸甲基转移酶 7 （PRMT7） 通过与 MAVS 相互作用并催化 MAVS 中精氨酸 232 （R232me1） 的单甲基化，作为 I 型 IFN 信号通路的负调节因子。RNA 病毒感染导致 PRMT7 与 MAVS 的下调和解离以及 R232me1 甲基化的减少，从而增强 MAVS/RIG-I 相互作用、MAVS 聚集、I 型 IFN 信号激活和抗病毒免疫反应。由于抗病毒免疫反应增强，用赖氨酸 （Mavs R232K -KI） 取代 MAVS R232 的敲入小鼠对水泡性口炎病毒感染更具抵抗力。PiPRMT7-MAVS 是一种短肽抑制剂，旨在中断 PRMT7 和 MAVS 之间的相互作用，抑制 R232me1 甲基化，从而增强 MAVS/RIG-I 相互作用，促进 MAVS 聚集，激活 I 型 IFN 信号传导，并增强抗病毒免疫反应以抑制 RNA 病毒复制。此外，PRMT7 的临床相关性突出，因为它在 RNA 病毒感染的临床样本中显着下调，例如来自严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 和埃博拉病毒的血液样本，以及 H1N1 感染的支气管上皮细胞。 我们的研究结果发现，PRMT7 介导的精氨酸甲基化在调节 MAVS 介导的抗病毒先天免疫反应中起关键作用，靶向精氨酸甲基化可能代表了治疗 RNA 病毒感染的治疗途径。