School of Life Sciences, Tianjin University, Tianjin, 300072, China.
Tianjin Heping District Hospital of Obstetrics and Gynecology, 300041, China.
Virology. 2019 Jun;532:55-68. doi: 10.1016/j.virol.2019.04.004. Epub 2019 Apr 15.
Porcine reproductive and respiratory syndrome virus (PRRSV) can potently suppress type I interferon production and escape from innate immune responses. PRRSV nonstructural protein 1α (Nsp1α) can inhibit IFN-β and NF-κB gene promoter activities, but the precise mechanisms are largely unclear. In this study, we demonstrated that PRRSV Nsp1α interacted with the host E3 ubiquitin ligase ankyrin repeat and SOCS box-containing 8 (ASB8). Specifically, porcine ASB8 promoted K63-linked ubiquitination and increased stability of Nsp1α and boosted PRRSV replication. Moreover, we found that ASB8 was phosphorylated at the N-terminal Ser-31 by host IκB kinase β (IKKβ). In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKβ via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IκBα) and of p65 phosphorylation, consequently suppressing NF-κB activity. Our results provide evidence that PRRSV Nsp1α hijacks up-regulated host ASB8 to escape from intrinsic antiviral immunity.
猪繁殖与呼吸综合征病毒（PRRSV）能够强烈抑制 I 型干扰素的产生并逃避先天免疫反应。PRRSV 的非结构蛋白 1α（Nsp1α）能够抑制 IFN-β 和 NF-κB 基因启动子活性，但确切的机制在很大程度上尚不清楚。在本研究中，我们证明 PRRSV Nsp1α 与宿主 E3 泛素连接酶锚蛋白重复和 SOCS 盒包含蛋白 8（ASB8）相互作用。具体而言，猪 ASB8 促进了 Nsp1α 的 K63 连接泛素化和稳定性增加，并促进了 PRRSV 的复制。此外，我们发现宿主 IκB 激酶 β（IKKβ）在 N 端 Ser-31 位点使 ASB8 磷酸化。反过来，ASB8 通过泛素-蛋白酶体途径促进 IKKβ 的 K48 连接泛素化和降解，从而显著抑制 IκBα 和 p65 磷酸化，进而抑制 NF-κB 活性。我们的研究结果表明，PRRSV Nsp1α 劫持了上调的宿主 ASB8，以逃避固有抗病毒免疫。
