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.