Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling

ABSTRACT TANK-binding kinase 1 (TBK1) is a key component of the antiviral immunity signaling pathway. It activates downstream interferon regulatory factor 3 (IRF3) and subsequent type I interferon (IFN-I) production. Herpes simplex virus type 1 (HSV-1) can antagonize host antiviral immune responses...

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Autores principales:	Hongjuan You, Sisilia Zheng, Zhiming Huang, Yingying Lin, Qingtang Shen, Chunfu Zheng
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	HSV-1 IRF3 TBK1 UL46 type I IFN Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bc0e7657b172407fb6e2c8adc64da309
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spelling	oai:doaj.org-article:bc0e7657b172407fb6e2c8adc64da3092021-11-15T15:55:23ZHerpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling10.1128/mBio.00919-192150-7511https://doaj.org/article/bc0e7657b172407fb6e2c8adc64da3092019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00919-19https://doaj.org/toc/2150-7511ABSTRACT TANK-binding kinase 1 (TBK1) is a key component of the antiviral immunity signaling pathway. It activates downstream interferon regulatory factor 3 (IRF3) and subsequent type I interferon (IFN-I) production. Herpes simplex virus type 1 (HSV-1) can antagonize host antiviral immune responses and lead to latent infection. Here, HSV-1 tegument protein UL46 was demonstrated to downregulate TBK1-dependent antiviral innate immunity. UL46 interacted with TBK1 and reduced TBK1 activation and its downstream signaling. Our results showed that UL46 impaired the interaction of TBK1 and IRF3 and downregulated the activation of IRF3 by inhibiting the dimerization of TBK1 to reduce the IFN-I production induced by TBK1 and immunostimulatory DNA. The IFN-I and its downstream antiviral genes induced by UL46-deficient HSV-1 (ΔUL46 HSV-1) were higher than those of wild-type HSV-1 (WT HSV-1). In addition, the stable knockdown of TBK1 facilitated the replication of ΔUL46 HSV-1, but not WT HSV-1. Together, these findings reveal a novel mechanism of immune evasion by HSV-1. IMPORTANCE HSV-1 has evolved multiple strategies to evade host antiviral responses and establish a lifelong latent infection, but the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity are not completely understood. As TBK1 is very critical for antiviral innate immunity, it is of great interest to reveal the immune evasion mechanism of HSV-1 by targeting TBK1. In the present study, HSV-1 UL46 was found to inhibit the activation of IFN-I by targeting TBK1, suggesting that the evasion of TBK1 mediated antiviral innate immunity by HSV-1 UL46. Findings in this study will provide new insights into the host-virus interaction and help develop new approaches against HSV-1 infection.Hongjuan YouSisilia ZhengZhiming HuangYingying LinQingtang ShenChunfu ZhengAmerican Society for MicrobiologyarticleHSV-1IRF3TBK1UL46type I IFNMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	HSV-1 IRF3 TBK1 UL46 type I IFN Microbiology QR1-502
spellingShingle	HSV-1 IRF3 TBK1 UL46 type I IFN Microbiology QR1-502 Hongjuan You Sisilia Zheng Zhiming Huang Yingying Lin Qingtang Shen Chunfu Zheng Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
description	ABSTRACT TANK-binding kinase 1 (TBK1) is a key component of the antiviral immunity signaling pathway. It activates downstream interferon regulatory factor 3 (IRF3) and subsequent type I interferon (IFN-I) production. Herpes simplex virus type 1 (HSV-1) can antagonize host antiviral immune responses and lead to latent infection. Here, HSV-1 tegument protein UL46 was demonstrated to downregulate TBK1-dependent antiviral innate immunity. UL46 interacted with TBK1 and reduced TBK1 activation and its downstream signaling. Our results showed that UL46 impaired the interaction of TBK1 and IRF3 and downregulated the activation of IRF3 by inhibiting the dimerization of TBK1 to reduce the IFN-I production induced by TBK1 and immunostimulatory DNA. The IFN-I and its downstream antiviral genes induced by UL46-deficient HSV-1 (ΔUL46 HSV-1) were higher than those of wild-type HSV-1 (WT HSV-1). In addition, the stable knockdown of TBK1 facilitated the replication of ΔUL46 HSV-1, but not WT HSV-1. Together, these findings reveal a novel mechanism of immune evasion by HSV-1. IMPORTANCE HSV-1 has evolved multiple strategies to evade host antiviral responses and establish a lifelong latent infection, but the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity are not completely understood. As TBK1 is very critical for antiviral innate immunity, it is of great interest to reveal the immune evasion mechanism of HSV-1 by targeting TBK1. In the present study, HSV-1 UL46 was found to inhibit the activation of IFN-I by targeting TBK1, suggesting that the evasion of TBK1 mediated antiviral innate immunity by HSV-1 UL46. Findings in this study will provide new insights into the host-virus interaction and help develop new approaches against HSV-1 infection.
format	article
author	Hongjuan You Sisilia Zheng Zhiming Huang Yingying Lin Qingtang Shen Chunfu Zheng
author_facet	Hongjuan You Sisilia Zheng Zhiming Huang Yingying Lin Qingtang Shen Chunfu Zheng
author_sort	Hongjuan You
title	Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
title_short	Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
title_full	Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
title_fullStr	Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
title_full_unstemmed	Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling
title_sort	herpes simplex virus 1 tegument protein ul46 inhibits tank-binding kinase 1-mediated signaling
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/bc0e7657b172407fb6e2c8adc64da309
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Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling

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