Histone deacetylase 3 contributes to the anti-viral innate immunity of macrophages through interacting with FOXK1 to regulate STAT1/2 transcription [RNA-seq]. Histone deacetylase 3 contributes to the anti-viral innate immunity of macrophages through interacting with FOXK1 to regulate STAT1/2 transcription [RNA-seq]

It is well known that IFNα/β activates the JAK/STAT signaling pathway and suppresses viral replication through induction of interferon stimulated genes (ISGs). Here we reported that knockout of HDAC3 from macrophages resulted in decreased expression of STAT1 and STAT2, leading to a defective anti-viral immunity in cells and mice. Further studies showed that HDAC3 interacted with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localized with FOXK1 at the promoter of STAT1 and STAT2, and was required for protecting FOXK1 from lysosomal system mediated degradation. Constantly, FOXK1 deficient macrophages also showed low STAT1 and STAT2 expression with defective response to virus. Thus, our studies uncovered the biological importance of HDAC3 on regulating antiviral immunity of macrophages through interaction with FOXK1 to regulate the expression of STAT1 and STAT2. Overall design: Total RNA profiling of gene expression upon knock-out of Hdac3 or Foxk1 in RAW264.7 cells after stimulated with vesicular stomatitis virus for 8h

众所周知，干扰素α/β（IFNα/β）可激活JAK/STAT信号通路，并通过诱导干扰素刺激基因（interferon stimulated genes，ISGs）的表达抑制病毒复制。本研究发现，巨噬细胞中敲除组蛋白去乙酰化酶3（HDAC3）后，STAT1与STAT2的表达水平下调，导致细胞与小鼠的抗病毒免疫功能出现缺陷。进一步研究显示，HDAC3可与保守转录因子叉头框蛋白K1（FOXK1）发生相互作用，与FOXK1共定位至STAT1与STAT2的启动子区域，并可保护FOXK1免受溶酶体系统介导的降解。与此一致的是，FOXK1缺陷型巨噬细胞同样呈现出STAT1与STAT2的低表达状态，且对病毒的应答存在缺陷。综上，本研究揭示了HDAC3通过与FOXK1相互作用调控STAT1与STAT2的表达，进而调控巨噬细胞抗病毒免疫的生物学重要性。实验设计概要：将RAW264.7细胞经水疱性口炎病毒（vesicular stomatitis virus，VSV）刺激8小时后，对敲除Hdac3或Foxk1的该细胞系开展总RNA基因表达谱分析。