Table_1_Initial activation of STAT2 induced by IAV infection is critical for innate antiviral immunity.pdf

STAT2 is an important transcription factor activated by interferons (IFNs) upon viral infection and plays a key role in antiviral responses. Interestingly, here we found that phosphorylation of STAT2 could be induced by several viruses at early infection stage, including influenza A virus (IAV), and such initial activation of STAT2 was independent of type I IFNs and JAK kinases. Furthermore, it was observed that the early activation of STAT2 during viral infection was mainly regulated by the RIG-I/MAVS-dependent pathway. Disruption of STAT2 phosphorylation at Tyr690 restrained antiviral response, as silencing STAT2 or blocking STAT2 Y690 phosphorylation suppressed the expression of several interferon-stimulated genes (ISGs), thereby facilitating viral replication. In vitro experiments using overexpression system or kinase inhibitors showed that several kinases including MAPK12 and Syk were involved in regulation of the early phosphorylation of STAT2 triggered by IAV infection. Moreover, when MAPK12 kinase was inhibited, expression of several ISGs was clearly decreased in cells infected with IAV at the early infection stage. Accordingly, inhibition of MAPK12 accelerated the replication of influenza virus in host. These results provide a better understanding of how initial activation of STAT2 and the early antiviral responses are induced by the viral infection.

信号转导与转录激活因子2（STAT2）是一类可在病毒感染后被干扰素（interferons, IFNs）激活的重要转录因子，在抗病毒应答中发挥关键调控作用。值得关注的是，本研究发现多种病毒可在感染早期诱导STAT2发生磷酸化，其中涵盖甲型流感病毒（influenza A virus, IAV）；此类STAT2的初始激活并不依赖I型干扰素与JAK激酶（JAK kinases）。进一步研究表明，病毒感染期间STAT2的早期激活主要受RIG-I/MAVS依赖信号通路调控。若破坏STAT2在Tyr690位点的磷酸化，则会抑制抗病毒应答：敲低STAT2或阻断STAT2 Tyr690位点的磷酸化，可抑制多种干扰素刺激基因（interferon-stimulated genes, ISGs）的表达，进而促进病毒复制。体外实验中，利用过表达系统或激酶抑制剂开展的检测结果显示，MAPK12、Syk等多种激酶参与调控甲型流感病毒感染诱导的STAT2早期磷酸化过程。此外，当MAPK12激酶被抑制时，甲型流感病毒感染早期的细胞内多种ISGs的表达量显著下调；相应地，MAPK12的抑制会加速流感病毒在宿主内的复制。本研究结果为深入理解病毒感染诱导STAT2初始激活与早期抗病毒应答的机制提供了新的认知。