Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells
| Autor: | J. Andrejeva, Andri Vasou, David J. Hughes, John McLauchlan, Connor G. G. Bamford, David Holthaus, Christina Paulus, Richard E. Randall |
|---|---|
| Přispěvatelé: | Academy of Medical Sciences, The Wellcome Trust, University of St Andrews. School of Biology, University of St Andrews. Biomedical Sciences Research Complex |
| Rok vydání: | 2019 |
| Předmět: |
QH301 Biology
Immunology Innate Immunity and Inflammation NDAS Ubiquitin-Activating Enzymes Biology Negative regulator QH301 Gene Knockout Techniques 03 medical and health sciences 0302 clinical medicine Interferon Chlorocebus aethiops Protein biosynthesis medicine Immunology and Allergy Animals Humans Ubiquitins Vero Cells Gene Adaptor Proteins Signal Transducing Disease Resistance 030304 developmental biology QR355 0303 health sciences Gene knockdown Paramyxoviridae Infections Effector 030302 biochemistry & molecular biology virus diseases Interferon-alpha RNA-Binding Proteins Translation (biology) ISG15 Virology Parainfluenza Virus 2 Human Parainfluenza Virus 3 Human 3. Good health Tetratricopeptide A549 Cells Gene Knockdown Techniques Parainfluenza Virus 5 Cytokines QR355 Virology Protein Processing Post-Translational 030215 immunology Signal Transduction medicine.drug |
| Zdroj: | The Journal of Immunology Author Choice |
| DOI: | 10.1101/2019.12.12.873919 |
| Popis: | Key Points Cell culture model of ISG15 deficiency replicates findings in ISG15−/− patient cells. Cause of resistance in ISG15−/− cells differs depending on duration of IFN treatment. ISG15−/− patients without serious viral disease do not prove ISGylation is unimportant. IFNs, 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|