Seneca Valley virus 3C protease cleaves HDAC4 to antagonize type I interferon signaling.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-10 DOI:10.1128/jvi.02176-24
Zijian Li, Jingjing Yang, Ruiyi Ma, Shijie Xie, Dan Wang, Rong Quan, Xuexia Wen, Jue Liu, Jiangwei Song
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引用次数: 0

Abstract

Seneca Valley virus (SVV) is a newly identified pathogen that poses a notable threat to the global pig industry. SVV has evolved multiple strategies to evade host antiviral innate immune responses. However, the underlying molecular mechanisms have not yet been fully elucidated. Histone deacetylases (HDACs) have been shown to function as host antiviral innate immune factors. In this study, we examined the mechanisms underlying SVV evasion of host innate immunity and found that SVV infection induced degradation and cleavage of HDAC4. Ectopic expression of HDAC4 suppressed SVV replication, whereas siRNA-mediated knockdown of HDAC4 enhanced SVV replication. Further studies showed that the viral 3C protease (3Cpro) degraded HDAC4 in a protease activity- and caspase pathway-dependent manner. In addition, 3Cpro cleaved HDAC4 at Q599, which blocked its ability to limit viral replication. We also found that HDAC4 interacted with the SVV viral RNA-dependent RNA polymerase 3D and induced its proteasomal degradation. The cleaved HDAC4 products did not block SVV replication or induce 3D degradation and did not induce type I interferon (IFN) activation and expression of IFN-stimulated genes (ISGs). Collectively, these findings identified HDAC4 as an antiviral factor with effects against SVV infection and provided mechanistic insights into how SVV 3Cpro antagonizes its function, which has implications for viral evasion of innate immunity.

Importance: Seneca Valley virus (SVV) is an emerging pathogen that causes vesicular disease in pigs and poses a threat to the pork industry. Histone deacetylases (HDACs) are important in the regulation of innate immunity. However, little is known about their roles in SVV infection. Our results revealed HDAC4 as an anti-SVV infection factor that targets the viral RNA-dependent RNA polymerase, 3D, for degradation. The SVV proteinase 3Cpro targets HDAC4 for degradation and cleavage, and cleavage of HDAC4 abrogated its antiviral effect. HDAC4 promotes type I interferon (IFN) signaling, and SVV 3Cpro-mediated cleavage of HDAC4 antagonized induction of type I IFN and interferon-stimulated genes (ISGs). Our findings reveal a novel molecular mechanism by which SVV 3Cpro counteracts type I IFN signaling by targeting HDAC4.

塞内卡谷病毒3C蛋白酶裂解HDAC4以拮抗I型干扰素信号。
塞内卡谷病毒(SVV)是一种新发现的病原体,对全球养猪业构成显著威胁。SVV进化出多种策略来逃避宿主抗病毒先天免疫反应。然而,潜在的分子机制尚未完全阐明。组蛋白去乙酰化酶(hdac)已被证明具有宿主抗病毒先天免疫因子的功能。在这项研究中,我们研究了SVV逃避宿主先天免疫的机制,发现SVV感染诱导HDAC4的降解和裂解。异位表达HDAC4抑制SVV复制,而sirna介导的HDAC4敲低则增强SVV复制。进一步的研究表明,病毒3C蛋白酶(3Cpro)以蛋白酶活性和半胱天冬酶途径依赖的方式降解HDAC4。此外,3Cpro在Q599处切割HDAC4,阻断其限制病毒复制的能力。我们还发现HDAC4与SVV病毒RNA依赖的RNA聚合酶3D相互作用并诱导其蛋白酶体降解。切割后的HDAC4产物不会阻断SVV复制或诱导3D降解,也不会诱导I型干扰素(IFN)的激活和IFN刺激基因(ISGs)的表达。总的来说,这些发现确定了HDAC4是一种抗病毒因子,对SVV感染有作用,并提供了SVV 3Cpro如何拮抗其功能的机制见解,这对病毒逃避先天免疫有影响。重要性:塞内卡谷病毒(SVV)是一种引起猪水疱病的新兴病原体,对猪肉工业构成威胁。组蛋白去乙酰化酶(hdac)在先天免疫调节中起重要作用。然而,人们对它们在SVV感染中的作用知之甚少。我们的研究结果表明,HDAC4是一种抗svv感染因子,可靶向病毒RNA依赖性RNA聚合酶3D进行降解。SVV蛋白酶3Cpro以HDAC4为靶点进行降解和裂解,HDAC4的裂解使其抗病毒作用失效。HDAC4促进I型干扰素(IFN)信号传导,SVV 3cpro介导的HDAC4裂解可拮抗诱导I型IFN和干扰素刺激基因(ISGs)。我们的研究结果揭示了SVV 3Cpro通过靶向HDAC4来对抗I型IFN信号的一种新的分子机制。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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