Pseudorabies Virus EP0 Antagonizes the Type I Interferon Response via Inhibiting IRF9 Transcription
- 13 July 2022
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 96 (13), e0217121
- https://doi.org/10.1128/jvi.02171-21
Abstract
Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. The alphaherpesvirus pseudorabies virus (PRV) is the etiologic agent of swine Aujeszky's disease, which can cause huge economic losses to the pig industry. PRV can overcome a type I interferon (IFN)-induced antiviral state in host cells through its encoded EP0 protein. However, the exact role of EP0 in this process is poorly defined. Here, we report that EP0 transcriptionally represses IFN regulatory factor 9 (IRF9), a critical component in the IFN signaling pathway, thereby reducing the cellular levels of IRF9 and inhibiting IFN-induced gene transcription. This activity of EP0 is mediated by its C-terminal region independently of the RING domain. Moreover, compared with EP0 wild-type PRV, EP0-deficient PRV loses the ability to efficiently decrease cellular IRF9, while reintroducing the C-terminal region of EP0 back into the EP0-deficient virus restores the activity. Together, these results suggest that EP0 can transcriptionally modulate IRF9-mediated antiviral pathways through its C-terminal region, contributing to PRV innate immune evasion. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that alphaherpesvirus can utilize its encoded early protein EP0 to inhibit the IFN-induced upregulation of antiviral proteins by reducing the basal expression levels of IRF9 through repressing its transcription. Our findings reveal a mechanism employed by alphaherpesvirus to evade the immune response and indicate that EP0 is an important viral protein in pathogenesis and a potential target for antiviral drug development.Keywords
Funding Information
- Key R&D Program of Shandong Province (2020CXGC010503)
- CAU-Grant for the Prevention and Control of Immunosuppressive Diseases in Aminals
- National Natural Science Foundation of China (32172829)
- National Natural Science Foundation of China (32072848)
This publication has 48 references indexed in Scilit:
- Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 InflammasomesJournal of Virology, 2013
- Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 proteinProceedings of the National Academy of Sciences of the United States of America, 2012
- Herpes Simplex Virus 1 Ubiquitin Ligase ICP0 Interacts with PML Isoform I and Induces Its SUMO-Independent DegradationJournal of Virology, 2012
- STAT-Phosphorylation–Independent Induction of Interferon Regulatory Factor-9 by Interferon-βJournal of Interferon & Cytokine Research, 2010
- Recognition of viruses by cytoplasmic sensorsCurrent Opinion in Immunology, 2010
- Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9Journal of Virology, 2009
- Control of TANK-binding Kinase 1-mediated Signaling by the γ134.5 Protein of Herpes Simplex Virus 1Online Journal of Public Health Informatics, 2009
- Interferon-inducible antiviral effectorsNature Reviews Immunology, 2008
- Pseudorabies Virus EP0 Protein Counteracts an Interferon-Induced Antiviral State in a Species-Specific MannerJournal of Virology, 2006
- The Human Papillomavirus Type 16 E7 Protein Binds Human Interferon Regulatory Factor-9 via a Novel PEST Domain Required for TransformationJournal of Interferon & Cytokine Research, 2006