Herpes Simplex Virus 1 UL2 Inhibits the TNF-α–Mediated NF-κB Activity by Interacting With p65/p50

Mingsheng Cai,Yuanfang Wang,Meili Li,Tong Li,Zuo Xu,Yangxi Deng,Tao Peng,Xiaowen Ou,Yiwen Li,Xingmei Zou,Yingjie Guo,Zongmin Liao

doi:10.3389/fimmu.2020.00549

Abstract

Herpes simplex virus 1 (HSV-1) is a large double-stranded DNA virus that encodes at least 80 viral proteins, many of which are involved in the virus–host interaction and are beneficial to the viral survival and reproduction. However, the biological functions of some HSV-1–encoded proteins are not fully understood. Nuclear factor κB (NF-κB) activation is the major antiviral innate response, which can be triggered by various signals induced by cellular receptors from different pathways. Here, we demonstrated that HSV-1 UL2 protein could antagonize the tumor necrosis factor α (TNF-α)–mediated NF-κB activation. Co-immunoprecipitation assays showed that UL2 could interact with the NF-κB subunits p65 and p50, which also revealed the region of amino acids 9 to 17 of UL2 could suppress the NF-κB activation and interact with p65 and p50, and UL2 bound to the immunoglobulin-like plexin transcription factor functional domain of p65. However, UL2 did not affect the formation of p65/p50 dimerization and their nuclear localizations. Yet, UL2 was demonstrated to inhibit the NF-κB activity by attenuating TNF-α–induced p65 phosphorylation at Ser536 and therefore decreasing the expression of downstream inflammatory chemokine interleukin 8. Taken together, the attenuation of NF-κB activation by UL2 may contribute to the escape of host’s antiviral innate immunity for HSV-1 during its infection.

Highlights

Herpes simplex virus 1 (HSV-1) is an important human pathogen, which is carried with high frequencies in the world with its well-known ability to establish a lifelong latent infection in neurons and trigger a reactivation and lytic infection mainly in human epithelial or mucosal cells [1]
uracil DNA glycosylase (UDG) may be dispensable for the viral replication in culture cells, UDG mutant exhibits reduced neurovirulence, and a decreased frequency of reactivation from latency, indicating that UDG may be vital for HSV-1 reactivation in quiescent neuronal cells, during which the genome might accumulate uracil as a result of spontaneous deamination of cytosine [5, 11]
tumor necrosis factor α (TNF-α) can be rapidly recognized by tumor necrosis factor receptor (TNFR) when stimulus signal acts on cells and induces the activation of canonical NF-κB pathway [35]

Summary

Introduction

Herpes simplex virus 1 (HSV-1) is an important human pathogen, which is carried with high frequencies in the world with its well-known ability to establish a lifelong latent infection in neurons and trigger a reactivation and lytic infection mainly in human epithelial or mucosal cells [1]. UDG may be dispensable for the viral replication in culture cells, UDG mutant exhibits reduced neurovirulence, and a decreased frequency of reactivation from latency, indicating that UDG may be vital for HSV-1 reactivation in quiescent neuronal cells, during which the genome might accumulate uracil as a result of spontaneous deamination of cytosine [5, 11]. UL2 may play a significant role in the virulence, latency, and reactivation of HSV-1 infection [11, 16,17,18]. The exact roles of UL2 during HSV-1 infection are still poorly understood

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Discussion

Conclusion