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dc.contributor.authorGuerra, Susana-
dc.contributor.authorCáceres, Ana-
dc.contributor.authorKnobeloch, Klaus-Peter-
dc.contributor.authorHorak, Ivan-
dc.contributor.authorEsteban, Mariano-
dc.date.accessioned2008-11-26T16:14:02Z-
dc.date.available2008-11-26T16:14:02Z-
dc.date.issued2008-07-04-
dc.identifier.citationPLoS Pathog 4(7): e1000096en_US
dc.identifier.issn1553-7366-
dc.identifier.urihttp://hdl.handle.net/10261/8832-
dc.description16 pages, 10 figures.-- PMID: 18604270 [PubMed].-- PMCID: PMC2434199.-- Supporting material available: Figure S1: Effect of ISG15 overexpression on virus citotoxicity after infection of MEFs with virulent and E3L deletion VACV mutant viruses. Table S1: Levels of ISG15 mRNA detected by quantitative realtime RT-PCR after infection of HeLa cells with several VACV mutants.en_US
dc.description.abstract[Abstract] The ubiquitin-like modifier ISG15 is one of the most predominant proteins induced by type I interferons (IFN). In this study, murine embryo fibroblast (MEFs) and mice lacking the gene were used to demonstrate a novel role of ISG15 as a host defense molecule against vaccinia virus (VACV) infection. In MEFs, the growth of replication competent Western Reserve (WR) VACV strain was affected by the absence of ISG15, but in addition, virus lacking E3 protein (VVΔE3L) that is unable to grow in ISG15+/+ cells replicated in ISG15-deficient cells. Inhibiting ISG15 with siRNA or promoting its expression in ISG15−/− cells with a lentivirus vector showed that VACV replication was controlled by ISG15. Immunoprecipitation analysis revealed that E3 binds ISG15 through its C-terminal domain. The VACV antiviral action of ISG15 and its interaction with E3 are events independent of PKR (double-stranded RNA-dependent protein kinase). In mice lacking ISG15, infection with VVΔE3L caused significant disease and mortality, an effect not observed in VVΔE3L-infected ISG15+/+ mice. Pathogenesis in ISG15-deficient mice infected with VVΔE3L or with an E3L deletion mutant virus lacking the C-terminal domain triggered an enhanced inflammatory response in the lungs compared with ISG15+/+-infected mice. These findings showed an anti-VACV function of ISG15, with the virus E3 protein suppressing the action of the ISG15 antiviral factor.en_US
dc.description.abstract[Author summary] Modification of proteins by ubiquitin (UB) and ubiquitin-like proteins (UBL) represents a key regulatory process of innate and adaptive immune responses. Interferon-stimulated gene product 15 (ISG15) is a member of UBL molecules that can reversibly be conjugated to proteins mediating considerable antiviral response. In turn, many viruses, including poxviruses, have evolved strategies to block the antiviral and inflammatory effects of innate immune responses to keep cells alive until virus replication is completed. Here, a novel viral immune evasion mechanism that inhibits ISG15-dependent antiviral pathway is described. Vaccinia virus (VACV) pathogenesis in ISG15+/+ versus ISG15−/− mice is linked to the virus E3 protein, blocking the activity of ISG15 through its C-terminal domain. This effect was independent of PKR activation. ISG15 controls the inflammatory response regulating cytokine levels. Our findings support a new strategy for poxviruses to evade the host antiviral response through interaction of the virus E3 protein with ISG15.en_US
dc.description.sponsorshipThe work was supported by the Ramón y Cajal program from Ministry of Education and Science of Spain and grants from the European Union, QLK2-CT-2002-01867 (Vaccinia Vectors), LSHP-CT-2006-037536 (MVACTOR), and Fundación Botín.en_US
dc.format.extent2174789 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofPublisher’s version-
dc.rightsopenAccessen_US
dc.subjectVaccinia virus (VACV)en_US
dc.subjectType I interferons (IFN)en_US
dc.subjectImmune responseen_US
dc.subjectInterferon-stimulated gene product 15 (ISG15)en_US
dc.subjectMurine embryo fibroblast (MEFs)en_US
dc.subjectViral immune evasion mechanismsen_US
dc.subjectVirus E3 proteinen_US
dc.subjectPoxvirusesen_US
dc.titleVaccinia Virus E3 Protein Prevents the Antiviral Action of ISG15en_US
dc.typeartículoen_US
dc.identifier.doi10.1371/journal.ppat.1000096-
dc.description.peerreviewedPeer revieweden_US
dc.relation.publisherversionhttp://dx.doi.org/10.1371/journal.ppat.1000096en_US
dc.identifier.e-issn1553-7374-
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