title: Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo.
abstract: The innate immune response, and in particular the alpha/beta interferon (IFN-alpha/beta) system, plays a critical role in the control of viral infections. Interferons alpha and beta exert their antiviral effects through the induction of hundreds of interferon-induced (or -stimulated) genes (ISGs). While several of these ISGs have characterized antiviral functions, their actions alone do not explain all of the effects mediated by IFN-alpha/beta. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-alpha/beta receptor (IFN-alpha/betaR)(-/-) mice and looked for attenuation of Sindbis virus infection. Using this approach, we identified a ubiquitin homolog, interferon-stimulated gene 15 (ISG15), as having antiviral activity. ISG15 expression protected against Sindbis virus-induced lethality and decreased Sindbis virus replication in multiple organs without inhibiting the spread of virus throughout the host. We establish that, much like ubiquitin, ISG15 requires its C-terminal LRLRGG motif to form intracellular conjugates. Finally, we demonstrate that ISG15's LRLRGG motif is also required for its antiviral activity. We conclude that ISG15 can be directly antiviral.
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
authors.forename: Nadia V
authors.initials: NV
authors.lastname: Giannakopoulos
authors.forename: Lacey J
authors.initials: LJ
authors.lastname: Gunn
authors.forename: Christine
authors.initials: C
authors.lastname: Johnston
authors.forename: Andy K
authors.initials: AK
authors.lastname: O'Guin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D018354:Alphavirus Infections / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016898:Interferon-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016899:Interferon-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D012845:Sindbis Virus / Q000235:genetics* / Q000472:pathogenicity; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D014452:Ubiquitins; D016899:Interferon-beta