U.S. Department of Defense


Date of this Version



Cell Host & Microbe 2, 404–416, December 200


This article is a U.S. government work, and is not subject to copyright in the United States.


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. Weshowthat theOTUdomain-containing proteases fromnairoviruses and arteriviruses, two unrelated groups ofRNAviruses, hydrolyzeUb and ISG15 from cellular target proteins. This broad activity contrasts with the target specificity of knownmammalianOTUdomain-containing proteins. Expression of a viralOTUdomain-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 NFkB- dependent signaling. Thus, the deconjugating activity of viral OTU proteases represents a unique viral strategy to inhibit Ub- and ISG15- dependent antiviral pathways.