Ovarian Tumor Domain-Containing Viral Proteases Evade Ubiquitin- and ISG15-Dependent Innate Immune Responses

Natalia Frias-Staheli, Nadia V. Giannakopoulos, Marjolein Kikkert, Shannon L. Taylor, Anne Bridgen, Jason Paragas, Juergen A. Richt, Raymond R. Rowland, Connie S. Schmaljohn, Deborah J. Lenschow, Eric J. Snijder, Adolfo García-Sastre, Herbert Whiting Virgin IV

Research output: Contribution to journalArticlepeer-review


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-κB-dependent signaling. Thus, the deconjugating activity of viral OTU proteases represents a unique viral strategy to inhibit Ub- and ISG15-dependent antiviral pathways.

Original languageEnglish (US)
Pages (from-to)404-416
Number of pages13
JournalCell Host and Microbe
Issue number6
StatePublished - Dec 13 2007
Externally publishedYes



ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology


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