title: Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses.
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. 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.
authors: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: Natalia
authors: N
authors: Frias-Staheli
authors: Nadia V
authors: NV
authors: Giannakopoulos
authors: Marjolein
authors: M
authors: Kikkert
authors: Shannon L
authors: SL
authors: Taylor
authors: Anne
authors: A
authors: Bridgen
authors: Jason
authors: J
authors: Paragas
authors: Juergen A
authors: JA
authors: Richt
authors: Raymond R
authors: RR
authors: Rowland
authors: Connie S
authors: CS
authors: Schmaljohn
authors: Deborah J
authors: DJ
authors: Lenschow
authors: Eric J
authors: EJ
authors: Snijder
authors: Adolfo
authors: A
authors: García-Sastre
authors: Herbert Whiting
authors: HW
authors: Virgin
mesh_terms: 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*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009363:Neoplasm Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D014764:Viral Proteins; C074034:ISG15 protein, human; D010447:Peptide Hydrolases