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

生物 先天免疫系统 HDAC4型 病毒复制 干扰素 细胞生物学 炎症体 基因敲除 病毒 组蛋白 Ⅰ型干扰素 病毒学 组蛋白脱乙酰基酶 免疫系统 免疫学 遗传学 基因 炎症
作者
Zijian Li,Jianjun Yang,Ruiyi Ma,Shijie Xie,Dan Wang,Rong Quan,Xuexia Wen,Jue Liu,Jiangwei Song
出处
期刊:Journal of Virology [American Society for Microbiology]
标识
DOI:10.1128/jvi.02176-24
摘要

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 (3C pro ) degraded HDAC4 in a protease activity- and caspase pathway-dependent manner. In addition, 3C pro 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 3C pro 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.
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