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Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells

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Date
22/06/2020
Author
Holthaus, David
Vasou, Andri
Bamford, Connor
Andrejeva, Jelena
Paulus, Christina
Randall, Richard Edward
McLauchlan, John
Hughes, David John
Funder
Academy of Medical Sciences
The Wellcome Trust
Grant ID
SBF003/1028
101788/Z/13/Z
Keywords
QH301 Biology
QR355 Virology
NDAS
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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.
Citation
Holthaus , 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 . https://doi.org/10.4049/jimmunol.1901472
Publication
The Journal of Immunology
Status
Peer reviewed
DOI
https://doi.org/10.4049/jimmunol.1901472
ISSN
0022-1767
Type
Journal article
Rights
Copyright © 2020 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license.
Description
This 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.).
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  • University of St Andrews Research
URL
https://www.biorxiv.org/content/10.1101/2019.12.12.873919v2
URI
http://hdl.handle.net/10023/20010

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