Li, C; Zhang, M; Guan, X; Hu, H; Fu, M; Liu, Y; Hu, Q
(2021)
Herpes Simplex Virus Type 2 Glycoprotein D Inhibits NF-κB Activation by Interacting with p65.
The Journal of Immunology, 206 (12).
pp. 2852-2861.
ISSN 0022-1767
https://doi.org/10.4049/jimmunol.2001336
SGUL Authors: Hu, Qinxue
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Abstract
NF-κB plays a crucial role in regulating cell proliferation, inflammation, apoptosis, and immune responses. HSV type 2 (HSV-2) is one of the most predominant sexually transmitted pathogens worldwide, and its infection increases the risk of HIV type 1 (HIV-1) acquisition and transmission. HSV-2 glycoprotein D (gD), highly homologous to HSV-1 gD, is essential for viral adhesion, fusion, entry, and spread. It is known that HSV-1 gD can bind herpesvirus entry mediator (HVEM) to trigger NF-κB activation and thereby facilitate viral replication at the early stage of infection. In this study, we found that purified HSV-2 gD triggered NF-κB activation at the early stage of infection, whereas ectopic expression of HSV-2 gD significantly downregulated TNF-α–induced NF-κB activity as well as TNF-α–induced IL-6 and IL-8 expression. Mechanistically, HSV-2 gD inhibited NF-κB, but not IFN-regulatory factor 3 (IRF3), activation and suppressed NF-κB activation mediated by overexpression of TNFR-associated factor 2 (TRAF2), IκB kinase α (IKKα), IKKβ, or p65. Coimmunoprecipitation and binding kinetic analyses demonstrated that HSV-2 gD directly bound to the NF-κB subunit p65 and abolished the nuclear translocation of p65 upon TNF-α stimulation. Mutational analyses further revealed that HSV-2 gD interacted with the region spanning aa 19–187 of p65. Findings in this study together demonstrate that HSV-2 gD interacts with p65 to regulate p65 subcellular localization and thereby prevents NF-κB–dependent gene expression, which may contribute to HSV-2 immune evasion and pathogenesis.
Item Type: | Article | ||||||||
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Keywords: | 1107 Immunology, Immunology | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) | ||||||||
Journal or Publication Title: | The Journal of Immunology | ||||||||
ISSN: | 0022-1767 | ||||||||
Language: | en | ||||||||
Dates: |
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Publisher License: | Publisher's own licence | ||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/113295 | ||||||||
Publisher's version: | https://doi.org/10.4049/jimmunol.2001336 |
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