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

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Florine E.M. Scholte, Marko Zivcec, John V. Dzimianski, Michelle K. Deaton, Jessica R. Spengler, Stephen R. Welch, Stuart T. Nichol, Scott D. Pegan, Christina F. Spiropoulou, Éric Bergeron
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.

Graphical abstract

Teaser

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.


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