State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
The Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China.
Front Immunol. 2019 Jun 25;10:1432. doi: 10.3389/fimmu.2019.01432. eCollection 2019.
Neddylation is a type of post-translational protein modifications, in which neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) is covalently conjugated to the lysine residues of target substrates. The best characterized principal substrates of neddylation are the cullin-RING ligases (CRLs). In addition, neddylation also modifies non-cullin proteins to affect gene regulation, cell survival, organ development, and stress response. However, the role of neddylation in antiviral innate immunity remain largely unknown. Here, we found that when neddylation was blocked by the NEDD8 activating enzyme E1 (NAE) inhibitor, MLN4924, the cellular and organismal antiviral response was suppressed. Moreover, the disruption of increased the sensitivity of zebrafish to SVCV infection. Further assays indicated that blocking or silencing neddylation significantly downregulated key antiviral genes after poly (I:C) stimulation or SVCV infection, but dramatically increased SVCV replication. Neddylation of Irf3 and Irf7 was readily detected, but not of Mda5, Mavs, and Tbk1. Thus, our results not only demonstrated that neddylation facilitated the antiviral response and , but also revealed a novel role of in antiviral innate immunity.
泛素化是一种翻译后蛋白质修饰方式，其中神经前体细胞表达发育下调蛋白 8（NEDD8）通过共价键与靶底物的赖氨酸残基结合。泛素化的最佳特征主要底物是 Cullin-RING 连接酶（CRLs）。此外，泛素化还修饰非 Cullin 蛋白，以影响基因调控、细胞存活、器官发育和应激反应。然而，泛素化在抗病毒先天免疫中的作用在很大程度上仍然未知。在这里，我们发现当 NEDD8 激活酶 E1（NAE）抑制剂 MLN4924 阻断泛素化时，细胞和机体抗病毒反应受到抑制。此外，破坏增加了斑马鱼对 SVCV 感染的敏感性。进一步的测定表明，在 poly（I:C）刺激或 SVCV 感染后，阻断或沉默泛素化显著下调了关键的抗病毒基因，但显著增加了 SVCV 复制。很容易检测到 Irf3 和 Irf7 的泛素化，但 Mda5、Mavs 和 Tbk1 则不然。因此，我们的结果不仅表明泛素化促进了抗病毒反应，而且还揭示了在抗病毒先天免疫中一个新的作用。
