猪繁殖与呼吸综合症病毒（PRRSV）是一种外包膜正股RNA病毒，在全球范围内给养猪业造成严重的经济损失。I型干扰素诱导干扰素刺激基因15（ISG15）的表达以抑制病毒复制。为了在寄主中生存，PRRSV已进化出对ISGylation的抗病毒反应。先前的研究报告称，PRRSV的非结构性蛋白质2依赖卵巢肿瘤(Ovarian tumor, OTU)结构域/蛋白酶（protease）2区，抑制了ISGylation和ISG15的抗病毒功能。然而，是否还有其他PRRSV蛋白质抑制ISGylation细胞蛋白质的作用机制尚不清楚。在本研究中，我们首次发现PRRSV Nsp11降低了细胞蛋白质的ISGylation。同时，Nsp11明显抑制ISG15的表达水平。进一步的机制研究表明，Nsp11的内切核酸酶作用降低了ISG15的转录。最后，我们发现Nsp11诱导的ISG15降解部分依赖于自噬-溶酶体系统。综上所述，PRRSV Nsp11通过其内切核酸酶活性，对抗ISG15的抗病毒反应，从而促进PRRSV的复制。我们的研究结果揭示了一种新的机制，即PRRSV抑制细胞蛋白质的ISGylation并破坏宿主的先天免疫反应。版权所有©2023 Elsevier B.V.。

Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped positive-stranded RNA virus which causes serious economic losses to pig industry worldwide. Type I IFN induces expression of interferon-stimulated genes 15 (ISG15) to inhibit virus replication. To survive in the host, PRRSV has evolved to antagonize the antiviral response of ISGylation. Previous studies have reported that nonstructural protein 2 of PRRSV inhibits the ISGylation and antiviral function of ISG15 depending on its ovarian tumor (OTU) domain/papain-like protease domain (PLP2). However, whether there are other PRRSV proteins inhibiting ISGylation of cellular proteins is less well understood. In this study, we first found that PRRSV Nsp11 decreased ISGylation of cellular proteins. Meanwhile, the expression level of ISG15 was significantly inhibited by Nsp11. Further mechanistic studies demonstrated that the transcription of ISG15 was reduced by endoribonuclease activity of Nsp11. Finally, we found that the Nsp11-induced degradation of ISG15 was partially relied on autophagy-lysosome system. Taken together, PRRSV Nsp11 antagonizes the antiviral response of ISG15 by its endoribonuclease activity to promote PRRSV replication. Our results reveal a novel mechanism that PRRSV inhibits ISGylation of cellular proteins and impairs host innate immune response.Copyright © 2023 Elsevier B.V. All rights reserved.