Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses.
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-kappaB-dependent signaling. Thus, the deconjugating activity of viral OTU proteases represents a unique viral strategy to inhibit Ub- and ISG15-dependent antiviral pathways.
Frias-Staheli
Natalia
N
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Giannakopoulos
Nadia V
NV
Kikkert
Marjolein
M
Taylor
Shannon L
SL
Bridgen
Anne
A
Paragas
Jason
J
Richt
Juergen A
JA
Rowland
Raymond R
RR
Schmaljohn
Connie S
CS
Lenschow
Deborah J
DJ
Snijder
Eric J
EJ
García-Sastre
Adolfo
A
Virgin
Herbert Whiting
HW
D018354:Alphavirus Infections / Q000276:immunology / Q000821:virology; D000595:Amino Acid Sequence; D000818:Animals; D018018:Arterivirus / Q000201:enzymology / Q000235:genetics; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D016855:Nairovirus / Q000201:enzymology / Q000235:genetics; D009363:Neoplasm Proteins / Q000502:physiology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology*; D016415:Sequence Alignment; D015398:Signal Transduction; D012845:Sindbis Virus / Q000201:enzymology; D025801:Ubiquitin / Q000276:immunology* / Q000378:metabolism; D014452:Ubiquitins / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000502:physiology*
D016207:Cytokines; D016328:NF-kappa B; D009363:Neoplasm Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D014764:Viral Proteins; C074034:ISG15 protein, human; D010447:Peptide Hydrolases