TY - JOUR
T1 - Ovarian Tumor Domain-Containing Viral Proteases Evade Ubiquitin- and ISG15-Dependent Innate Immune Responses
AU - Frias-Staheli, Natalia
AU - Giannakopoulos, Nadia V.
AU - Kikkert, Marjolein
AU - Taylor, Shannon L.
AU - Bridgen, Anne
AU - Paragas, Jason
AU - Richt, Juergen A.
AU - Rowland, Raymond R.
AU - Schmaljohn, Connie S.
AU - Lenschow, Deborah J.
AU - Snijder, Eric J.
AU - García-Sastre, Adolfo
AU - Virgin IV, Herbert Whiting
N1 - Funding Information:
We thank Richard Cadagan, Caroline Lai, and Lindsay Droit for technical assistance; Dr. Domenico Tortorella for helpful discussions; and Drs. Dong-Er Zhang, Motoaki Ohtsubo, Adrian Ting, and Dianne Griffin for providing reagents. This work was partially supported by DoD grants W81XWH-04-1-0876 and W81XWH-07-2-0028, and by a NIAID-funded Center to Investigate Virus Immunity and Antagonism (CIVIA) U19 AI62623 (to A.G.-S.), and by NIAID grants U54 AI057160 Projects 6 and 10 (to H.W.V.) and U54 AI057158 (to A.G.-S.).
PY - 2007/12/13
Y1 - 2007/12/13
N2 - 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.
AB - 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.
KW - MICROBIO
KW - MOLIMMUNO
KW - PROTEINS
UR - http://www.scopus.com/inward/record.url?scp=36749007273&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2007.09.014
DO - 10.1016/j.chom.2007.09.014
M3 - Article
C2 - 18078692
AN - SCOPUS:36749007273
SN - 1931-3128
VL - 2
SP - 404
EP - 416
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -