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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\u2212\/\u2212 cells and (using A549-UBA7\u2212\/\u2212 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-\u03b1 were resistant to paramyxovirus infection. We also showed that IFN-\u03b1 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-\u03b1\u2013pretreated, 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-\u03b1 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1901472","type":"journal-article","created":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T15:49:34Z","timestamp":1589816974000},"page":"261-271","source":"Crossref","is-referenced-by-count":17,"title":["Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7012-5605","authenticated-orcid":false,"given":"David","family":"Holthaus","sequence":"first","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andri","family":"Vasou","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor G G","family":"Bamford","sequence":"additional","affiliation":[{"name":"MRC-University of Glasgow Centre for Virus Research , Glasgow G61 1QH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Andrejeva","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4123-5629","authenticated-orcid":false,"given":"Christina","family":"Paulus","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9304-6678","authenticated-orcid":false,"given":"Richard E","family":"Randall","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2217-9948","authenticated-orcid":false,"given":"John","family":"McLauchlan","sequence":"additional","affiliation":[{"name":"MRC-University of Glasgow Centre for Virus Research , Glasgow G61 1QH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-5710","authenticated-orcid":false,"given":"David J","family":"Hughes","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex, School of Biology, University of St Andrews , St Andrews KY16 9ST ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,1]]},"reference":[{"key":"2025030417504188100_r1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.coviro.2016.11.012","article-title":"Protect this house: cytosolic sensing of viruses","volume":"22","author":"McFadden","year":"2017","journal-title":"Curr. 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