Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Room 2341, Bethesda, MD, 20892, USA.
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, 6 Center Drive, Room 2A01, Bethesda, MD, 20892, USA.
Nat Commun. 2018 Mar 20;9(1):1145. doi: 10.1038/s41467-018-03326-5.
Control of type I interferon production is crucial to combat infection while preventing deleterious inflammatory responses, but the extent of the contribution of post-transcriptional mechanisms to innate immune regulation is unclear. Here, we show that human zinc finger RNA-binding protein (ZFR) represses the interferon response by regulating alternative pre-mRNA splicing. ZFR expression is tightly controlled during macrophage development; monocytes express truncated ZFR isoforms, while macrophages induce full-length ZFR to modulate macrophage-specific alternative splicing. Interferon-stimulated genes are constitutively activated by ZFR depletion, and immunostimulation results in hyper-induction of interferon β (IFNβ/IFNB1). Through whole-genome analyses, we show that ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay of histone variant macroH2A1/H2AFY mRNAs. Together, our data suggest that regulation of ZFR in macrophage differentiation guards against aberrant interferon responses and reveal a network of mRNA processing and decay that shapes the transcriptional response to infection.
控制 I 型干扰素的产生对于对抗感染和防止有害的炎症反应至关重要，但转录后机制对先天免疫调节的贡献程度尚不清楚。在这里，我们表明，人类锌指 RNA 结合蛋白 (ZFR) 通过调节选择性前体 mRNA 剪接来抑制干扰素反应。ZFR 的表达在巨噬细胞发育过程中受到严格控制；单核细胞表达截断的 ZFR 异构体，而巨噬细胞诱导全长 ZFR 来调节巨噬细胞特异性选择性剪接。干扰素刺激基因被 ZFR 耗竭持续激活，免疫刺激导致干扰素 β（IFNβ/IFNB1）的过度诱导。通过全基因组分析，我们表明 ZFR 通过防止组蛋白变体 macroH2A1/H2AFY mRNAs 的异常剪接和无意义介导的衰变来控制干扰素信号。总之，我们的数据表明，ZFR 在巨噬细胞分化中的调控可以防止干扰素反应的异常，并揭示了一个 mRNA 加工和降解的网络，该网络塑造了对感染的转录反应。
