From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and.
the University of Chinese Academy of Sciences, Beijing 101408, China.
J Biol Chem. 2019 Jun 14;294(24):9503-9517. doi: 10.1074/jbc.RA118.006563. Epub 2019 Apr 30.
Heartland virus (HRTV) is a pathogenic phlebovirus recently identified in the United States and related to severe fever with thrombocytopenia syndrome virus (SFTSV) emerging in Asia. We previously reported that SFTSV disrupts host antiviral responses directed by interferons (IFNs) and their downstream regulators, signal transducer and activator of transcription (STAT) proteins. However, whether HRTV infection antagonizes the IFN-STAT signaling axis remains unclear. Here, we show that, similar to SFTSV, HRTV also inhibits IFN-α- and IFN-λ-mediated antiviral responses. As expected, the nonstructural protein (NSs) of HRTV (HNSs) robustly antagonized both type I and III IFN signaling. Protein interaction analyses revealed that a common component downstream of type I and III IFN signaling, STAT2, is the target of HNSs. Of note, the DNA-binding and linker domains of STAT2 were required for an efficient HNSs-STAT2 interaction. Unlike the NSs of SFTSV (SNSs), which blocks both STAT2 and STAT1 nuclear accumulation, HNSs specifically blocked IFN-triggered nuclear translocation only of STAT2. However, upon HRTV infection, IFN-induced nuclear translocation of both STAT2 and STAT1 was suppressed, suggesting that STAT1 is an additional HRTV target for IFN antagonism. Consistently, despite HNSs inhibiting phosphorylation only of STAT2 and not STAT1, HRTV infection diminished both STAT2 and STAT1 phosphorylation. These results suggest that HRTV antagonizes IFN antiviral signaling by dampening both STAT2 and STAT1 activities. We propose that HNSs-specific targeting of STAT2 likely plays an important role but is not all of the "tactics" of HRTV in its immune evasion.
心脏地带病毒（HRTV）是一种最近在美国发现的致病性黄病毒，与亚洲出现的严重发热伴血小板减少综合征病毒（SFTSV）有关。我们之前报道过 SFTSV 破坏了由干扰素（IFNs）及其下游调节剂信号转导和转录激活因子（STAT）蛋白介导的宿主抗病毒反应。然而，HRTV 感染是否拮抗 IFN-STAT 信号轴尚不清楚。在这里，我们表明，与 SFTSV 相似，HRTV 也抑制 IFN-α和 IFN-λ介导的抗病毒反应。正如预期的那样，HRTV 的非结构蛋白（NSs）（HNSs）强烈拮抗 I 型和 III 型 IFN 信号。蛋白相互作用分析表明，I 型和 III 型 IFN 信号的下游常见成分 STAT2 是 HNSs 的靶标。值得注意的是，STAT2 的 DNA 结合和连接域是 HNSs-STAT2 有效相互作用所必需的。与 SFTSV 的 NSs（SNSs）不同，SNSs 阻断 STAT2 和 STAT1 的核积累，HNSs 特异性地仅阻断 IFN 触发的 STAT2 核易位。然而，在 HRTV 感染后，IFN 诱导的 STAT2 和 STAT1 的核易位均被抑制，表明 STAT1 是 IFN 拮抗的另一个 HRTV 靶标。一致地，尽管 HNSs 仅抑制 STAT2 而不抑制 STAT1 的磷酸化，但 HRTV 感染减少了 STAT2 和 STAT1 的磷酸化。这些结果表明，HRTV 通过抑制 STAT2 和 STAT1 的活性来拮抗 IFN 抗病毒信号。我们提出，HNSs 对 STAT2 的特异性靶向可能发挥了重要作用，但并非 HRTV 免疫逃避的所有“策略”。
