Frias-Staheli Natalia, Giannakopoulos Nadia V, Kikkert Marjolein, Taylor Shannon L, Bridgen Anne, Paragas Jason, Richt Juergen A, Rowland Raymond R, Schmaljohn Connie S, Lenschow Deborah J, Snijder Eric J, García-Sastre Adolfo, Virgin Herbert Whiting
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cell Host Microbe. 2007 Dec 13;2(6):404-16. doi: 10.1016/j.chom.2007.09.014.
Ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15) reversibly conjugate to proteins and mediate important innate antiviral responses. The ovarian tumor (OTU) domain represents a superfamily of predicted proteases found in eukaryotic, bacterial, and viral proteins, some of which have Ub-deconjugating activity. We show that the OTU domain-containing proteases from nairoviruses and arteriviruses, two unrelated groups of RNA viruses, hydrolyze Ub and ISG15 from cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domain-containing proteins. Expression of a viral OTU domain-containing protein antagonizes the antiviral effects of ISG15 and enhances susceptibility to Sindbis virus infection in vivo. We also show that viral OTU domain-containing proteases inhibit NF-kappaB-dependent signaling. Thus, the deconjugating activity of viral OTU proteases represents a unique viral strategy to inhibit Ub- and ISG15-dependent antiviral pathways.
泛素（Ub）和干扰素刺激基因产物15（ISG15）可与蛋白质可逆结合，并介导重要的先天性抗病毒反应。卵巢肿瘤（OTU）结构域代表了一个在真核生物、细菌和病毒蛋白中发现的预测蛋白酶超家族，其中一些具有去泛素化活性。我们发现，内罗病毒和动脉病毒这两类不相关的RNA病毒中含OTU结构域的蛋白酶可从细胞靶蛋白上水解Ub和ISG15。这种广泛的活性与已知含哺乳动物OTU结构域蛋白的靶标特异性形成对比。表达含病毒OTU结构域的蛋白可拮抗ISG15的抗病毒作用，并增强体内对辛德毕斯病毒感染的易感性。我们还发现，含病毒OTU结构域的蛋白酶可抑制核因子κB依赖性信号传导。因此，病毒OTU蛋白酶的去结合活性代表了一种独特的病毒策略，用于抑制Ub和ISG15依赖性抗病毒途径。
