Assessment of deubiquitinating and deISGylating activity; specificity motifs amon

描述（由申请人提供）：克里米亚-刚果出血热（CCHF）病毒是一种ssRNA（-）奈罗病毒，可导致人类发热、乏力和严重出血。根据病毒的系统发育变异、传播途径和不同的治疗设施，CCHF的致死率在5-70%之间。CCHF最初在俄罗斯和刚果被发现，现已迅速蔓延到欧洲、亚洲和非洲的大部分地区。最近，前往受CCHF影响地区，特别是中南亚地区的美国公民交通量大幅增加。因此，存在将CCHF和/或其蜱虫媒介传播到美国的重大风险。目前，没有可用于治疗CCHF的疫苗或预防措施。最近的报道已经确定了卵巢肿瘤蛋白酶（vOTU）的病毒同源物，并暗示其可能通过切割翻译后修饰蛋白泛素（Ub）和Ub样干扰素刺激基因15 （ISG15）参与干扰素1型免疫应答的下调。此外，vOTU的低序列同源同源物已被认为在具有经济破坏性的ssRNA（+）动脉病毒、猪呼吸与繁殖综合征和马动脉炎中发挥类似的作用。本研究将确定去泛素化和去ISG15化活性是否是该蛋白酶亚类的保守功能，并深入了解它们对Ub和ISG15的识别机制。由此产生的信息将提供对不同病毒中votu功能的深入了解，最终可能在开发针对votu的预防措施方面具有实用性。

DESCRIPTION (provided by applicant): Crimean-Congo hemorrhagic fever (CCHF) virus is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates for CCHF range from 5-70% based on phylogenetic variation of the virus, transmission route, and different treatment facilities. Originally identified in Russia and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recently, U.S. citizen traffic has increased substantially to the regions affected by CCHF, specifically South Central Asia. As a result, there is a substantial risk for transmission of CCHF and/or its tick vector to the U.S. Currently, there is no vaccine or prophylactic available for treatment of CCHF. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) and implicated its possible involvement in down-regulation of the Interferon type 1 immune response through cleavage of post-translational modifying proteins ubiquitin (Ub) and Ub-like interferon-stimulated gene 15 (ISG15). Additionally, a low sequence homology homologue of vOTU has been suggested to perform a similar role in the economically devastating ssRNA (+) arteriviruses, Porcine Respiratory and Reproduction Syndrome and Equine arteritis. This proposal will determine whether deubiquitinating and deISGylating activity is conserved function of this subclass of protease as well as gain insight into their mechanism of recognition for Ub and ISG15. The resulting information will provide insight into the function of vOTUs in different viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs.