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dc.contributor.authorHolthaus, David
dc.contributor.authorVasou, Andri
dc.contributor.authorBamford, Connor
dc.contributor.authorAndrejeva, Jelena
dc.contributor.authorPaulus, Christina
dc.contributor.authorRandall, Richard Edward
dc.contributor.authorMcLauchlan, John
dc.contributor.authorHughes, David John
dc.identifier.citationHolthaus , D , Vasou , A , Bamford , C , Andrejeva , J , Paulus , C , Randall , R E , McLauchlan , J & Hughes , D J 2020 , ' Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells ' , The Journal of Immunology .
dc.identifier.otherPURE: 267631875
dc.identifier.otherPURE UUID: 13c7d65c-a322-4fc4-9a7b-0ef91a54b8c4
dc.identifier.otherPubMed: 32423918
dc.identifier.otherORCID: /0000-0002-9304-6678/work/74872888
dc.identifier.otherORCID: /0000-0003-4051-4658/work/74873021
dc.identifier.otherORCID: /0000-0002-0090-5710/work/74873054
dc.identifier.otherORCID: /0000-0002-4123-5629/work/74873059
dc.identifier.otherWOS: 000543320100025
dc.identifier.otherScopus: 85088395207
dc.descriptionThis work was supported by Academy of Medical Sciences Grant SBF003/1028, Wellcome Trust Grant 101788/Z/13/Z, U.K. Research and Innovation, Medical Research Council Grant MC_UU_12014/1, and Erasmus+ (to D.H.).en
dc.description.abstractIFNs, produced during viral infections, induce the expression of hundreds of IFN-stimulated genes (ISGs). Some ISGs have specific antiviral activity, whereas others regulate the cellular response. Besides functioning as an antiviral effector, ISG15 is a negative regulator of IFN signaling, and inherited ISG15 deficiency leads to autoinflammatory IFNopathies, in which individuals exhibit elevated ISG expression in the absence of pathogenic infection. We have recapitulated these effects in cultured human A549-ISG15−/− cells and (using A549-UBA7−/− cells) confirmed that posttranslational modification by ISG15 (ISGylation) is not required for regulation of the type I IFN response. ISG15-deficient cells pretreated with IFN-α were resistant to paramyxovirus infection. We also showed that IFN-α treatment of ISG15-deficient cells led to significant inhibition of global protein synthesis, leading us to ask whether resistance was due to the direct antiviral activity of ISGs or whether cells were nonpermissive because of translation defects. We took advantage of the knowledge that IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) is the principal antiviral ISG for parainfluenza virus 5. Knockdown of IFIT1 restored parainfluenza virus 5 infection in IFN-α–pretreated, ISG15-deficient cells, confirming that resistance was due to the direct antiviral activity of the IFN response. However, resistance could be induced if cells were pretreated with IFN-α for longer times, presumably because of inhibition of protein synthesis. These data show that the cause of virus resistance is 2-fold; ISG15 deficiency leads to the early overexpression of specific antiviral ISGs, but the later response is dominated by an unanticipated, ISG15-dependent loss of translational control.
dc.relation.ispartofThe Journal of Immunologyen
dc.rightsCopyright © 2020 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license.en
dc.subjectQH301 Biologyen
dc.subjectQR355 Virologyen
dc.titleDirect antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cellsen
dc.typeJournal articleen
dc.contributor.sponsorAcademy of Medical Sciencesen
dc.contributor.sponsorThe Wellcome Trusten
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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