|Whiting Virgin Iv, Herbet|
Submitted to: Cell Host and Microbe
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/21/2007
Publication Date: 12/13/2007
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.