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

Authors

• Adolfo Garcia-Sastre, Department of MicrobiologyFollow
• Herbert Whiting Virgin, Department of Pathology and Immunology, Department of Molecular MicrobiologyFollow
• Natalia Frias-Staheli, Department of Microbiology
• Nadia Giannakopoulos, Department of Pathology and Immunology, Department of Molecular Microbiology
• Marjolein Kikkert, Leiden University Medical Center
• Shannon Taylor, United States Army Medical Research Institute for Infectious Diseases,
• Anne Bridgen, University of Ulster
• Jason Pargas, National Institute of Allergy and Infectious Diseases
• Juergen Richt, National Animal Disease Center-ARS-USDA
• Raymond Rowland, Kansas State University
• Connie Schmaljohn, United States Army Medical Research Institute for Infectious Diseases,Follow
• Deborah Lenschow, Department of Pathology and Immunology, Department of Molecular Microbiology
• Eric Snijder, Leiden University Medical Center,

Document Type

Article

Date of this Version

2007

Citation

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

Comments

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

Abstract

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.