Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Microbiol. 2024 Apr;9(4):988-1006. doi: 10.1038/s41564-024-01646-5. Epub 2024 Mar 27.
The human facilitates chromatin transcription (FACT) complex is a chromatin remodeller composed of human suppressor of Ty 16 homologue (hSpt16) and structure-specific recognition protein-1 subunits that regulates cellular gene expression. Whether FACT regulates host responses to infection remained unclear. We identify a FACT-mediated, interferon-independent, antiviral pathway that restricts poxvirus replication. Cell culture and bioinformatics approaches suggest that early viral gene expression triggers nuclear accumulation of SUMOylated hSpt16 subunits required for the expression of E26 transformation-specific sequence-1 (ETS-1)-a transcription factor that activates virus restriction programs. However, biochemical studies show that poxvirus-encoded A51R proteins block ETS-1 expression by outcompeting structure-specific recognition protein-1 binding to SUMOylated hSpt16 and by tethering SUMOylated hSpt16 to microtubules. Furthermore, A51R antagonism of FACT enhances poxvirus replication in human cells and virulence in mice. Finally, we show that FACT also restricts rhabdoviruses, flaviviruses and orthomyxoviruses, suggesting broad roles for FACT in antiviral immunity. Our study reveals the FACT-ETS-1 antiviral response (FEAR) pathway to be critical for eukaryotic antiviral immunity and describes a unique mechanism of viral immune evasion.
人源转录辅助因子（FACT）复合物是一种染色质重塑因子，由人 Ty 16 抑制因子同源物（hSpt16）和结构特异性识别蛋白-1 亚基组成，可调节细胞基因表达。FACT 是否调节宿主对感染的反应尚不清楚。我们确定了一种 FACT 介导的、干扰素非依赖的抗病毒途径，该途径限制了痘病毒的复制。细胞培养和生物信息学方法表明，早期病毒基因表达触发了 SUMO 化 hSpt16 亚基的核积累，这对于 E26 转化特异性序列-1（ETS-1）的表达是必需的，ETS-1 是一种激活病毒限制程序的转录因子。然而，生化研究表明，痘病毒编码的 A51R 蛋白通过与 SUMO 化 hSpt16 竞争结合结构特异性识别蛋白-1，以及通过将 SUMO 化 hSpt16 固定在微管上来阻断 ETS-1 的表达。此外，A51R 拮抗 FACT 增强了人细胞中的痘病毒复制和小鼠中的毒力。最后，我们表明 FACT 还限制了弹状病毒、黄病毒和正粘病毒，这表明 FACT 在抗病毒免疫中具有广泛的作用。我们的研究揭示了 FACT-ETS-1 抗病毒反应（FEAR）途径对于真核抗病毒免疫至关重要，并描述了一种独特的病毒免疫逃避机制。
