E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-β and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.

E3泛素连接酶对于调节病毒感染期间的抗病毒免疫非常重要。在这里，我们发现锚蛋白重复序列​​和含有 SOCS 盒的蛋白 3 (ASB3)（一种 E3 连接酶）在 RNA 病毒，特别是甲型流感病毒 (IAV) 存在的情况下上调。值得注意的是，ASB3 的过度表达会抑制仙台病毒 (SeV) 和 IAV 诱导的 I 型干扰素 (IFN-I) 反应，而 ASB3 的消除可恢复 SeV 和 H9N2 感染介导的 IFN-β 及其下游干扰素刺激基因 (ISG) 的转录。 ）。有趣的是，缺乏 ASB3 的动物对 H9N2 和 H1N1 感染的易感性降低。从机制上讲，ASB3 与 MAVS 相互作用，直接介导 K48 连接的多泛素化和 MAVS 在 K297 处的降解，从而抑制 TBK1 和 IRF3 的磷酸化并下调下游抗病毒信号传导。这些发现确立了 ASB3 作为控制抗病毒信号激活的关键负调节因子，并描述了 ASB3 的一种以前未报道过的新功能。