Gomes Marco Túlio R, Guimarães Erika S, Oliveira Sergio C
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Immunol. 2025 Jan 9;15:1511949. doi: 10.3389/fimmu.2024.1511949. eCollection 2024.
The innate immune system promptly detects and responds to invading pathogens, with a key role played by the recognition of bacterial-derived DNA through pattern recognition receptors. The Z-DNA binding protein 1 (ZBP1) functions as a DNA sensor inducing type I interferon (IFN) production, innate immune responses and also inflammatory cell death. ZBP1 interacts with cytosolic DNA via its DNA-binding domains, crucial for its activation. is the etiologic agent of brucellosis in livestock and humans, leading to significant economic losses and public health impact. Despite other innate immune sensors that recognize DNA, including Toll-like receptor 9 and the Stimulator of interferon genes (STING), here we evaluated the ZBP1 participation as a cytosolic receptor sensing infection. Using macrophages derived from ZBP1 knockout (KO) mice we demonstrated that ZBP1 partially contributes to expression upon infection or DNA transfection. The knockdown of STING by siRNA decreased the residual IFN-β signal elicited by infection, demonstrating the presence of a redundant cytosolic DNA-sensing mechanism driving type I IFN production. Furthermore, ZBP1 is involved in type I IFN signaling inducing expression. Additionally, ZBP1 also contributes to Unfolded Protein Response (UPR) activation during infection. However, ZBP1 does not influence the production of proinflammatory mediators, inflammasome activation and it is dispensable to control bacterial infection in mice or replication in macrophages. This study highlights the complex interactions of components with innate immune receptors and identifies ZBP1 as a sensor for DNA-induced IFN-β response.
天然免疫系统能迅速检测并对入侵病原体做出反应，通过模式识别受体识别细菌来源的DNA发挥关键作用。Z-DNA结合蛋白1（ZBP1）作为一种DNA传感器，可诱导I型干扰素（IFN）产生、引发天然免疫反应以及导致炎症性细胞死亡。ZBP1通过其DNA结合结构域与胞质DNA相互作用，这对其激活至关重要。布鲁氏菌是家畜和人类布鲁氏菌病的病原体，会导致重大经济损失和公共卫生影响。尽管存在其他识别布鲁氏菌DNA的天然免疫传感器，包括Toll样受体9和干扰素基因刺激物（STING），但在此我们评估了ZBP1作为一种感知布鲁氏菌感染的胞质受体的作用。利用来自ZBP1基因敲除（KO）小鼠的巨噬细胞，我们证明ZBP1在布鲁氏菌感染或转染布鲁氏菌DNA后对I型干扰素的表达有部分贡献。通过小干扰RNA敲低STING可降低布鲁氏菌感染引发的残余IFN-β信号，这表明存在一种驱动I型干扰素产生的冗余胞质DNA传感机制。此外，ZBP1参与I型干扰素信号传导，诱导干扰素刺激基因的表达。此外，ZBP1在感染过程中也有助于未折叠蛋白反应（UPR）的激活。然而，ZBP1不影响促炎介质的产生、炎性小体的激活，并且在控制小鼠体内细菌感染或巨噬细胞内细菌复制方面是可有可无 的。这项研究突出了布鲁氏菌成分与天然免疫受体之间复杂的相互作用，并确定ZBP1是布鲁氏菌DNA诱导的IFN-β反应的传感器。
