Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, and Shanghai Institute of Infectious Disease and Biosecurity, Fudan University , Shanghai, China.
Shanghai Public Health Clinical Center, Fudan University , Shanghai, China.
Microbiol Spectr. 2024 Jan 11;12(1):e0360923. doi: 10.1128/spectrum.03609-23. Epub 2023 Nov 29.
Zika virus (ZIKV) is a re-emerging flavivirus. Similar to other flaviviruses, ZIKV antagonizes the host interferon (IFN) signaling pathway to establish infection. Understanding the molecular mechanism by which ZIKV antagonizes IFN-induced antiviral signaling may lead to a new antiviral strategy by cracking the IFN antagonism. Flaviviruses have been reported to employ NS5-dependent and -independent mechanisms to block STAT2-mediated signaling, whereas whether flaviviruses target STAT1 remains controversial. Herein, we found that ZIKV infection triggered caspase-dependent cleavage of STAT1 at the aspartic acid 694 during late infection, whereas murine STAT1 (mSTAT1) was resistant to cleavage. Intriguingly, ectopically expressed cleavage-resistant human STAT1.D694A or complementation of cleavable mSTAT1.D695G exerted comparable anti-ZIKV activity with their counterparts, challenging the role of caspase-mediated STAT1 cleavage in the IFN antagonism in ZIKV-infected cells. These data may also imply a dominant role of the antagonism of STAT2 but not STAT1 in ZIKV-infected cells.
寨卡病毒（ZIKV）是一种重新出现的黄病毒。与其他黄病毒类似，ZIKV 拮抗宿主干扰素（IFN）信号通路以建立感染。了解 ZIKV 拮抗 IFN 诱导的抗病毒信号的分子机制可能会通过破解 IFN 拮抗作用而产生新的抗病毒策略。已经报道黄病毒利用 NS5 依赖和非依赖机制来阻断 STAT2 介导的信号，而黄病毒是否靶向 STAT1 仍然存在争议。在这里，我们发现 ZIKV 感染在晚期感染过程中触发了天冬氨酸 694 处依赖半胱氨酸的 caspase 介导的 STAT1 切割，而鼠源 STAT1（mSTAT1）则不易被切割。有趣的是，异位表达不易切割的人 STAT1.D694A 或补充可切割的 mSTAT1.D695G 与它们的对应物具有相当的抗 ZIKV 活性，这对 caspase 介导的 STAT1 切割在 ZIKV 感染细胞中的 IFN 拮抗作用提出了挑战。这些数据还可能暗示在 ZIKV 感染的细胞中，STAT2 的拮抗作用而不是 STAT1 的拮抗作用占主导地位。
