Purbey Prabhat K, Scumpia Philip O, Kim Peter J, Tong Ann-Jay, Iwamoto Keisuke S, McBride William H, Smale Stephen T
Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Immunity. 2017 Sep 19;47(3):421-434.e3. doi: 10.1016/j.immuni.2017.08.017.
Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.
环境损伤通常由多种传感器检测到，这些传感器激活不同的信号通路和转录调节因子，从而产生定制的转录输出。为了了解定制反应是如何协调的，我们研究了电离辐射（IR）在小鼠巨噬细胞中引发的炎症反应。RNA测序研究表明，大多数辐射诱导基因强烈依赖于少数几种传感器和信号通路中的一种，特别是DNA损伤诱导激酶ATM，它通过一种非典型的、依赖IRF1且不依赖STING的机制调控许多IR反应基因，包括干扰素反应基因。此外，与炎症的微生物诱导剂相比，由p53和NRF2激活的特定小基因集解释了对辐射的选择性反应。我们的研究结果表明，构成环境反应的基因通过高度选择性的特定传感机制被激活，并且它们确定了辐射反应中可能易受治疗干扰的不同组成部分。
