The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

最近出现的严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 是 COVID-19 持续全球大流行的病原体，可能会在感染早期引发免疫抑制，并在感染后期引发过度活跃的免疫反应；然而，潜在的机制还不是很清楚。在这里，我们证明了 SARS-CoV-2 核衣壳 (N) 蛋白双重调节先天免疫反应，即低剂量 N 蛋白抑制 I 型干扰素 (IFN-I) 信号传导和炎症细胞因子，而高剂量 N 蛋白促进IFN-I 信号和炎性细胞因子。从机制上讲，SARS-CoV-2 N 蛋白双重调节 IRF3、STAT1 和 STAT2 的磷酸化和核易位。此外，低剂量N蛋白与TRIM25结合可抑制视黄酸诱导基因I（RIG-I）的泛素化和活化。我们的研究结果揭示了 SARS-CoV-2 N 蛋白对先天免疫反应的调节机制，这将有助于了解 SARS-CoV-2 和其他 SARS 样冠状病毒的发病机制，以及制定更有效的控制 COVID- 19.