Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I   Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

doi:10.1128/JVI.01148-17

CORC > 北京大学 > 生命科学学院

	Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response
	Zhang, Rui ; Xu, Aotian ; Qin, Chao ; Zhang, Qiong ; Chen, Shifan ; Lang, Yue ; Wang, Mengdong ; Li, Chuang ; Feng, Wenhai ; Zhang, Rui ; Jiang, Zhengfan ; Tang, Jun
刊名	JOURNAL OF VIROLOGY
	2017
关键词	alphaherpesviruses interferon signaling type I interferon receptor 1 dUTPase UL50 pseudorabies virus NF-KAPPA-B INNATE IMMUNE-RESPONSE VARICELLA-ZOSTER-VIRUS SIGNALING PATHWAY PROTEIN-KINASE HORIZONTAL TRANSFER INHIBITION EVOLUTION GENE HERPESVIRUSES
DOI	10.1128/JVI.01148-17
英文摘要	Alphaherpesviruses that establish persistent infections rely partly on their ability to evade host antiviral responses, notably the type I interferon (IFN) response. However, the mechanisms employed by alphaherpesviruses to avoid this response are not well understood. Pseudorabies virus (PRV) is an economically important pathogen and a useful model system for studying alphaherpesvirus biology. To identify PRV proteins that antagonize type I IFN signaling, we performed a screen by using an IFN-stimulated response element reporter in the swine cell line CRL. Unexpectedly, we identified the dUTPase UL50 as a strong inhibitor. We confirmed that UL50 has the ability to inhibit type I IFN signaling by performing ectopic expression of UL50 in cells and deletion of UL50 in PRV. Mechanistically, UL50 impeded type I IFN-induced STAT1 phosphorylation, likely by accelerating lysosomal degradation of IFN receptor 1 (IFNAR1). In addition, this UL50 activity was independent of its dUTPase activity and required amino acids 225 to 253 in the C-terminal region. The UL50 encoded by herpes simplex virus 1 (HSV-1) also possessed similar activity. Moreover, UL50-deleted PRV was more susceptible to IFN than UL50-proficient PRV. Our results suggest that in addition to its dUTPase activity, the UL50 protein of alphaherpesviruses possesses the ability to suppress type I IFN signaling by promoting lysosomal degradation of IFNAR1, thereby contributing to immune evasion. This finding reveals UL50 as a potential antiviral target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that this alphaherpesvirus could utilize its encoded dUTPase UL50 to induce IFNAR1 degradation and inhibit type I IFN signaling in an enzymatic activity-independent manner. Our finding reveals a mechanism employed by an alphaherpesvirus to evade the immune response and indicates that UL50 is an important viral protein in pathogenesis and is a potential target for antiviral drug development.; National Key Research and Development Program of China [2016YFD0500100]; National Natural Science Foundation of China [31500703]; Project for Extramural Scientists of the State Key Laboratory of Agrobiotechnology [2015SKLAB6-12]; Chinese Universities Scientific Fund [2017QC042]; SCI(E); ARTICLE; 21; 91
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/484564]
专题	生命科学学院
推荐引用方式 GB/T 7714	Zhang, Rui,Xu, Aotian,Qin, Chao,et al. Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response[J]. JOURNAL OF VIROLOGY,2017.
APA	Zhang, Rui.,Xu, Aotian.,Qin, Chao.,Zhang, Qiong.,Chen, Shifan.,...&Tang, Jun.(2017).Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response.JOURNAL OF VIROLOGY.
MLA	Zhang, Rui,et al."Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response".JOURNAL OF VIROLOGY (2017).