Porcine reproductive and respiratory syndrome (PRRS) is a widespread economically devastating disease caused by PRRS virus (PRRSV). First recognized in the late 1980s, PRRSV is known to undergo somatic mutations and high frequency viral recombination, which leads to many diverse viral strains. This includes differences within viral virulence factors, such as the viral ovarian tumor domain (vOTU) protease, also referred to as the papain-like protease 2. These proteases down-regulate innate immunity by deubiquitinating proteins targeted by the cell for further processing and potentially also acting against interferon-stimulated genes (ISGs). Recently, vOTUs from vaccine derivative Ingelvac PRRS modified live virus (MLV) and the highly pathogenic PRRSV strain JXwn06 were biochemically characterized, revealing a marked difference in activity toward K63 linked polyubiquitin chains and a limited preference for interferon-stimulated gene product 15 (ISG15) substrates. To extend our research, the vOTUs from NADC31 (low virulence) and SDSU73 (moderately virulent) were biochemically characterized using a myriad of ubiquitin and ISG15 related assays. The K63 polyubiquitin cleavage activity profiles of these vOTUs were found to track with the established pathogenesis of MLV, NADC31, SDSU73, and JXwn06 strains. Fascinatingly, NADC31 demonstrated significantly enhanced activity toward ISG15 substrates compared to its counterparts. Utilizing this information and strain–strain differences within the vOTU encoding region, sites were identified that can modulate K63 polyubiquitin and ISG15 cleavage activities. This information represents the basis for new tools to probe the role of vOTUs in the context of PRRSV pathogenesis.

中文翻译：

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对泛素和干扰素刺激的基因产物15的猪繁殖与呼吸综合征病毒病毒卵巢肿瘤域蛋白酶特异性的见解

猪繁殖与呼吸综合征（PRRS）是由PRRS病毒（PRRSV）引起的一种广泛的经济破坏性疾病。PRRSV最早在1980年代末期被认识，已知会发生体细胞突变和高频率病毒重组，从而导致多种多样的病毒株。这包括病毒毒性因子之间的差异，例如病毒卵巢肿瘤结构域（vOTU）蛋白酶，也称为木瓜蛋白酶样蛋白酶2。这些蛋白酶通过去泛素化细胞靶向的蛋白以进一步加工，从而潜在地降低先天免疫力。也可对抗干扰素刺​​激的基因（ISG）。最近，对疫苗衍生物Ingelvac PRRS修饰的活病毒（MLV）和高致病性PRRSV株JXwn06的vOTU进行了生化表征，揭示了对K63连接的多聚泛素链的活性存在显着差异，并且对干扰素刺激的基因产物15（ISG15）底物的偏爱有限。为了扩展我们的研究，使用多种泛素和ISG15相关分析对NADC31（低毒力）和SDSU73（中毒）的vOTU进行了生化表征。发现这些vOTU的K63聚泛素切割活性谱与MLV，NADC31，SDSU73和JXwn06菌株的既定发病机理密切相关。令人着迷的是，与同类产品相比，NADC31对ISG15底物的活性大大增强。利用这些信息和vOTU编码区内的应变差异，确定了可调节K63多聚泛素和ISG15裂解活性的位点。