Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
Department of Immunology, Tufts University School of Medicine, Boston, MA.
J Exp Med. 2018 Dec 3;215(12):3136-3150. doi: 10.1084/jem.20181031. Epub 2018 Nov 15.
An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Recently, cellular nucleic acid-binding protein (CNBP) was identified as a regulator of nuclear factor-kappaB (NF-κB)-dependent proinflammatory cytokine gene expression. Here, we generated mice lacking CNBP and found that CNBP regulates a very restricted gene signature that includes IL-12β. CNBP resides in the cytosol of macrophages and translocates to the nucleus in response to diverse microbial pathogens and pathogen-derived products. -deficient macrophages induced canonical NF-κB/Rel signaling normally but were impaired in their ability to control the activation of c-Rel, a key driver of IL-12β gene transcription. The nuclear translocation and DNA-binding activity of c-Rel required CNBP. Lastly, -deficient mice were more susceptible to acute toxoplasmosis associated with reduced production of IL-12β, as well as a reduced T helper type 1 (Th1) cell IFN-γ response essential to controlling parasite replication. Collectively, these findings identify CNBP as important regulator of c-Rel-dependent IL-12β gene transcription and Th1 immunity.
诱导性炎症基因表达程序是抗菌防御的标志。最近，细胞核酸结合蛋白 (CNBP) 被鉴定为核因子-κB (NF-κB) 依赖性促炎细胞因子基因表达的调节剂。在这里，我们生成了缺乏 CNBP 的小鼠，并发现 CNBP 调节了一个非常受限的基因特征，包括 IL-12β。CNBP 存在于巨噬细胞的细胞质中，并在响应各种微生物病原体和病原体衍生产物时易位到细胞核。-缺陷巨噬细胞正常诱导经典 NF-κB/Rel 信号，但控制 c-Rel 激活的能力受损，c-Rel 是 IL-12β 基因转录的关键驱动因素。c-Rel 的核易位和 DNA 结合活性需要 CNBP。最后，-缺陷小鼠更容易发生急性弓形体病，与 IL-12β 的产生减少以及控制寄生虫复制所必需的辅助性 T 细胞 1 (Th1) IFN-γ 反应减少有关。总的来说，这些发现确定了 CNBP 是 c-Rel 依赖性 IL-12β 基因转录和 Th1 免疫的重要调节剂。
