Herpes Simplex Virus Type 2 Inhibits Type I IFN Signaling Mediated by the Novel E3 Ubiquitin Protein Ligase Activity of Viral Protein ICP22.
J Immunol
; 205(5): 1281-1292, 2020 09 01.
Article
em En
| MEDLINE
| ID: mdl-32699158
Type I IFNs play an important role in innate immunity against viral infections by inducing the expression of IFN-stimulated genes (ISGs), which encode effectors with various antiviral functions. We and others previously reported that HSV type 2 (HSV-2) inhibits the synthesis of type I IFNs, but how HSV-2 suppresses IFN-mediated signaling is less understood. In the current study, after the demonstration of HSV-2 replication resistance to IFN-ß treatment in human epithelial cells, we reveal that HSV-2 and the viral protein ICP22 significantly decrease the expression of ISG54 at both mRNA and protein levels. Likewise, us1 del HSV-2 (ICP22-deficient HSV-2) replication is more sensitive to IFN-ß treatment, indicating that ICP22 is a vital viral protein responsible for the inhibition of type I IFN-mediated signaling. In addition, overexpression of HSV-2 ICP22 inhibits the expression of STAT1, STAT2, and IFN regulatory factor 9 (IRF9), resulting in the blockade of ISG factor 3 (ISGF3) nuclear translocation, and mechanistically, this is due to ICP22-induced ubiquitination of STAT1, STAT2, and IRF9. HSV-2 ICP22 appears to interact with STAT1, STAT2, IRF9, and several other ubiquitinated proteins. Following further biochemical study, we show that HSV-2 ICP22 functions as an E3 ubiquitin protein ligase to induce the formation of polyubiquitin chains. Taken together, we demonstrate that HSV-2 interferes with type I IFN-mediated signaling by degrading the proteins of ISGF3, and we identify HSV-2 ICP22 as a novel E3 ubiquitin protein ligase to induce the degradation of ISGF3. Findings in this study highlight a new mechanism by which HSV-2 circumvents the host antiviral responses through a viral E3 ubiquitin protein ligase.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Virais
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Transdução de Sinais
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Herpes Genital
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Interferon beta
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Proteínas Imediatamente Precoces
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Herpesvirus Humano 2
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Ubiquitina-Proteína Ligases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China