State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China.
Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China.
EMBO Rep. 2024 Oct;25(10):4594-4624. doi: 10.1038/s44319-024-00256-w. Epub 2024 Sep 16.
As a RIG-I-like receptor, MDA5 plays a critical role in antiviral innate immunity by acting as a cytoplasmic double-stranded RNA sensor capable of initiating type I interferon pathways. Here, we show that RNF144B specifically interacts with MDA5 and promotes K27/K33-linked polyubiquitination of MDA5 at lysine 23 and lysine 43, which promotes autophagic degradation of MDA5 by p62. Rnf144b deficiency greatly promotes IFN production and inhibits EMCV replication in vivo. Importantly, Rnf144b mice has a significantly higher overall survival rate than wild-type mice upon EMCV infection. Collectively, our results identify RNF144B as a negative regulator of innate antiviral response by targeting CARDs of MDA5 and mediating autophagic degradation of MDA5.
作为一种 RIG-I 样受体，MDA5 在抗病毒先天免疫中发挥关键作用，作为一种能够启动 I 型干扰素途径的细胞质双链 RNA 传感器。在这里，我们表明 RNF144B 特异性地与 MDA5 相互作用，并促进 MDA5 在赖氨酸 23 和赖氨酸 43 处的 K27/K33 连接多泛素化，从而促进 p62 介导的 MDA5 的自噬降解。Rnf144b 缺陷极大地促进了 IFN 的产生，并抑制了体内 EMCV 的复制。重要的是，在 EMCV 感染后，Rnf144b 小鼠的总存活率明显高于野生型小鼠。总之，我们的研究结果表明，RNF144B 通过靶向 MDA5 的 CARD 并介导 MDA5 的自噬降解，作为先天抗病毒反应的负调控因子。
