Zhang, M; Fu, M; Li, M; Hu, H; Gong, S; Hu, Q
(2020)
Herpes Simplex Virus Type 2 Inhibits Type I IFN Signaling Mediated by the Novel E3 Ubiquitin Protein Ligase Activity of Viral Protein ICP22.
The Journal of Immunology, 205 (5).
pp. 1281-1292.
ISSN 0022-1767
https://doi.org/10.4049/jimmunol.2000418
SGUL Authors: Hu, Qinxue
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Abstract
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-β 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-β 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.
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