State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
J Virol. 2024 Jul 23;98(7):e0058524. doi: 10.1128/jvi.00585-24. Epub 2024 Jun 13.
Senecavirus A (SVA), a picornavirus, causes vesicular diseases and epidemic transient neonatal losses in swine, resulting in a multifaceted economic impact on the swine industry. SVA counteracts host antiviral response through multiple strategies facilitatng viral infection and transmission. However, the mechanism of how SVA modulates interferon (IFN) response remains elusive. Here, we demonstrate that SVA 3C protease (3C) blocks the transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway to antagonize type I IFN response. Mechanistically, 3C selectively cleaves and degrades STAT1 and STAT2 while does not target JAK1, JAK2, and IRF9, through its protease activity. Notably, SVA 3C cleaves human and porcine STAT1 on a Leucine (L)-Aspartic acid (D) motif, specifically L693/D694. In the case of STAT2, two cleavage sites were identified: glutamine (Q) 707 was identified in both human and porcine, while the second cleavage pattern differed, with residues 754-757 (Valine-Leucine-Glutamine-Serine motifs) in human STAT2 and Q758 in porcine STAT2. These cleavage patterns by SVA 3C partially differ from previously reported classical motifs recognized by other picornaviral 3C, highlighting the distinct characteristics of SVA 3C. Together, these results reveal a mechanism by which SVA 3C antagonizes IFN-induced antiviral response but also expands our knowledge about the substrate recognition patterns for picornaviral 3C.IMPORTANCESenecavirus A (SVA), the only member in the genus within the family, causes vesicular diseases in pigs that are clinically indistinguishable from foot-and-mouth disease (FMD), a highly contagious viral disease listed by the World Organization for Animal Health (WOAH). Interferon (IFN)-mediated antiviral response plays a pivotal role in restricting and controlling viral infection. Picornaviruses evolved numerous strategies to antagonize host antiviral response. However, how SVA modulates the JAK-STAT signaling pathway, influencing the type I IFN response, remains elusive. Here, we identify that 3C, a protease of SVA, functions as an antagonist for the IFN response. 3C utilizes its protease activity to cleave STAT1 and STAT2, thereby diminishing the host IFN response to promote SVA infection. Our findings underscore the significance of 3C as a key virulence factor in the antagonism of the type I signaling pathway during SVA infection.
塞尼卡病毒 A（SVA）是一种小 RNA 病毒科病毒，可引起猪的水疱病和流行性短暂性新生仔猪死亡，对养猪业造成多方面的经济影响。SVA 通过多种策略来对抗宿主的抗病毒反应，促进病毒感染和传播。然而，SVA 如何调节干扰素（IFN）反应的机制仍不清楚。在这里，我们证明 SVA 3C 蛋白酶（3C）阻断了 Janus 激酶-信号转导和转录激活因子（JAK-STAT）信号通路的转导，从而拮抗 I 型 IFN 反应。机制上，3C 通过其蛋白酶活性选择性切割和降解 STAT1 和 STAT2，而不针对 JAK1、JAK2 和 IRF9。值得注意的是，SVA 3C 在亮氨酸（L）-天冬氨酸（D）基序上切割人和猪的 STAT1，具体为 L693/D694。对于 STAT2，鉴定出两个切割位点：人源和猪源 STAT2 的 Q707 相同，而第二个切割模式不同，人源 STAT2 为 754-757（缬氨酸-亮氨酸-谷氨酰胺-丝氨酸基序），猪源 STAT2 为 Q758。SVA 3C 的这些切割模式与其他小 RNA 病毒 3C 识别的先前报道的经典基序部分不同，突出了 SVA 3C 的独特特征。总之，这些结果揭示了 SVA 3C 拮抗 IFN 诱导的抗病毒反应的机制，但也扩展了我们对小 RNA 病毒 3C 底物识别模式的认识。
塞尼卡病毒 A（SVA）是杯状病毒科杯状病毒属中唯一的成员，会引起猪的水疱病，临床上与高度传染性的口蹄疫（FMD）无法区分，口蹄疫是世界动物卫生组织（WOAH）列出的疾病。干扰素（IFN）介导的抗病毒反应在限制和控制病毒感染中起着关键作用。小 RNA 病毒进化出多种策略来拮抗宿主抗病毒反应。然而，SVA 如何调节 JAK-STAT 信号通路，影响 I 型 IFN 反应，仍然难以捉摸。在这里，我们发现 SVA 的蛋白酶 3C 是 IFN 反应的拮抗剂。3C 利用其蛋白酶活性切割 STAT1 和 STAT2，从而降低宿主 IFN 反应，促进 SVA 感染。我们的研究结果强调了 3C 在 SVA 感染过程中作为关键毒力因子拮抗 I 型信号通路的重要性。
