Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

• Published in: Cell reports (Cambridge) 2017-09, Vol.20 (10), p.2396-2407
• Main Authors: Scholte, Florine E.M., Zivcec, Marko, Dzimianski, John V., Deaton, Michelle K., Spengler, Jessica R., Welch, Stephen R., Nichol, Stuart T., Pegan, Scott D., Spiropoulou, Christina F., Bergeron, Éric
• Format: Article
• Language: English
• Subjects: Bunyavirus; Crimean-Congo hemorrhagic fever; Cytokines - genetics; Cytokines - metabolism; Deubiquitinating Enzymes - genetics; Deubiquitinating Enzymes - metabolism; Female; Hemorrhagic Fever Virus, Crimean-Congo - genetics; Hemorrhagic Fever Virus, Crimean-Congo - metabolism; Humans; innate immunity; interferon; interferon stimulated gene-15; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; reverse genetics; ubiquitin; Ubiquitin - metabolism; ubiquitin specific protease; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; Ubiquitins - genetics; Ubiquitins - metabolism; virus replication; Virus Replication - genetics; Virus Replication - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.040

Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines. [Display omitted] •OTU protease is critical for virus replication but dispensable for viral RNA synthesis•Mutating OTU selectively disrupts deubiquitinase and deISGylase activity•OTU deubiquitinase activity is critical for suppressing interferon expression•OTU deISGylase reverses interferon-induced protein ISGylation Using reverse genetics, Scholte et al. report that OTU catalytic activity is critical for Crimean-Congo hemorrhagic fever virus replication, and deubiquitinase activity suppresses the antiviral response to infection. These findings provide insights in the multifunctional properties of viral OTUs and support development of OTU-specific therapeutics.