Abstract
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.
Highlights
The innate immune response against pathogens is underpinned by the evolutionary conserved IFN system
We had observed that IFNa treatment of A549-ISG152/2 cells led to dramatic decreases in protein synthesis, between 24 and 48 h; it was not clear whether the initially reported virus resistance was due to defects in translation at the timepoint used in [14] or due to the direct antiviral activity of the IFN response
Using these cell lines in combination with a parainfluenza virus 5 (PIV5) infection model, we showed that infection of IFN-a–pretreated ISG15deficient cells in which IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) had been knocked down restored infection, confirming that at early times p.i., resistance was due to the direct antiviral activity of the IFN response
Summary
The innate immune response against pathogens is underpinned by the evolutionary conserved IFN system. Other antiviral ISGs, such as IFN-induced protein with tetratricopeptide repeats (IFIT) proteins, inhibit specific viruses, but for many, they are inconsequential [5]. The nature of the innate immune response necessitates the production of the complete spectrum of ISGs, albeit with a high degree of redundancy, as during a natural infection, the identity of the infecting virus is not known. This response is inevitably tightly regulated, as a dysregulated response leads to a suite of autoinflammatory diseases [7].
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