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United States Department of Agriculture

Agricultural Research Service

Research Project: SWINE VIRAL DISEASES PATHOGENESIS AND IMMUNOLOGY Title: Ovarian tumor (OTU)-domain containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses

Authors
item Frias-Staheli, Natalia - MOUNT SINAI SCHOOL MEDICI
item Giannakopoulos, Nadia - WASHINGTON UNIVERSITY MED
item Kikkert, Marjolein - LEIDEN UNIVERSITY MED CTR
item Taylor, Shannon - US ARMY MEDICAL RESEARCH
item Bridgen, Anne - UNIVERSITY OF ULSTER
item Paragas, Jason - NIAID, NIH
item Richt, Juergen
item Rowland, Raymon - KANSAS STATE UNIVERSITY
item Schmaljohn, Connie - US ARMY MEDICAL RESEARCH
item Lenschow, Deborah - WASHINGTON UNIVERSITY MED
item Snijder, Eric - MOUNT SINAI SCHOOL MEDICI
item Garcia-Sastre, Adolfo - MOUNT SINAI SCHOOL MEDICI
item Whiting Virgin Iv, Herbet - WASHINGTON UNIVERSITY MED

Submitted to: Cell Host and Microbe
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 21, 2007
Publication Date: December 13, 2007
Citation: Frias-Staheli, N., Giannakopoulos, N.V., Kikkert, M., Taylor, S.L., Bridgen, A., Paragas, J., Richt, J.A., Rowland, R.R., Schmaljohn, C.S., Lenschow, D.J., Snijder, E.J., Garcia-Sastre, A., Virgin, H.W. 4th. 2007. Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses. Cell Host and Microbe. 2(6):404-416.

Interpretive Summary: Antiviral innate immune responses are needed to protect animals and humans from viral infections. In this manuscript we have shown that defined viral proteins can neutralize the antiviral effects of the innate immune system and therefore enhance susceptibility of host cells to virus infection.

Technical Abstract: Ubiquitin (Ub) and interferon stimulated gene product 15 (ISG15) reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating 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 of nairoviruses and arteriviruses hydrolyze Ub and ISG15 from many cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domain-containing proteins. The biological significance of this activity of viral OTU domain-containing proteases was evidenced by their capacity to inhibit NF-kappaB dependent signaling and to antagonize the antiviral effects of ISG15 during Sindbis virus infection in vivo. The deconjugating activity of viral OTU proteases represents a novel viral immune evasion mechanism that inhibits Ub-and ISG15-dependent antiviral pathways.

Last Modified: 7/25/2014
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