Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1
Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1
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DOI：
10.1074/jbc.ra118.006563
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发表时间：
2019-06-14
影响因子：
4.8
通讯作者：
Ning, Yun-Jia
中科院分区：
文献类型：
--
作者：
Feng, Kuan;Deng, Fei;Ning, Yun-Jia
心脏地带病毒（HRTV）是最近在美国发现的一种致病性静脉病毒，与亚洲出现的发热伴血小板减少综合征病毒（SFTSV）有关。我们之前报道过SFTSV破坏干扰素（ifn）及其下游调节因子、信号换能器和转录激活因子（STAT）蛋白指导的宿主抗病毒反应。然而，HRTV感染是否拮抗IFN-STAT信号轴仍不清楚。在这里，我们表明，与SFTSV类似，HRTV也抑制IFN和IFN介导的抗病毒反应。正如预期的那样，HRTV （HNSs）的非结构蛋白（NSs）强有力地拮抗I型和III型IFN信号。蛋白质相互作用分析显示，I型和III型IFN信号下游的一个常见成分STAT2是HNSs的靶标。值得注意的是，HNSs-STAT2的有效相互作用需要STAT2的dna结合和连接域。与SFTSV的NSs （SNSs）不同，HNSs可以阻断STAT2和STAT1的核积累，而HNSs特异性地阻断ifn触发的STAT2的核易位。然而，在HRTV感染后，IFN诱导的STAT2和STAT1的核易位被抑制，这表明STAT1是IFN拮抗HRTV的另一个靶点。一致地，尽管HNSs仅抑制STAT2而不抑制STAT1的磷酸化，但HRTV感染降低了STAT2和STAT1的磷酸化。这些结果表明HRTV通过抑制STAT2和STAT1活性来拮抗IFN抗病毒信号。我们认为hnss特异性靶向STAT2可能在HRTV免疫逃避中发挥重要作用，但不是全部策略。
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-- and IFN--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.