AUTHOR=Li Ruizhen , Liu Wenli , Yin Xiangrui , Zheng Fangfang , Wang Zhenyu , Wu Xingchen , Zhang Xiaohua , Du Qian , Huang Yong , Tong Dewen TITLE=Brucella spp. Omp25 Promotes Proteasome-Mediated cGAS Degradation to Attenuate IFN-β Production JOURNAL=Frontiers in Microbiology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.702881 DOI=10.3389/fmicb.2021.702881 ISSN=1664-302X ABSTRACT=

Type I interferons (IFN), a family of cytokines widely expressed in various tissues, play important roles in anti-infection immunity. Nevertheless, it is not known whether Brucella spp. could interfere with IFN-I production induced by other pathogens. This study investigated the regulatory roles of Brucella outer membrane protein (Omp)25 on the IFN-I signaling pathway and found that Omp25 inhibited the production of IFN-β and its downstream IFN-stimulated genes induced by various DNA viruses or IFN-stimulatory DNA in human, murine, porcine, bovine, and ovine monocyte/macrophages or peripheral blood mononuclear cells. Brucella Omp25 suppressed the phosphorylation of stimulator of IFN genes (STINGs) and IFN regulatory factor 3 and nuclear translocation of phosphorylated IFN regulatory factor 3 in pseudorabies virus- or herpes simplex virus-1-infected murine, human, or porcine macrophages. Furthermore, we found that Brucella Omp25 promoted cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) degradation via the proteasome-dependent pathway, resulting in a decreased cyclic guanosine monophosphate–adenosine monophosphate production and downstream signaling activation upon DNA virus infection or IFN-stimulatory DNA stimulation. Mapping the predominant function domain of Omp25 showed that the amino acids 161 to 184 of Omp25 were required for Omp25-induced cGAS degradation, among which five amino acid residues (R176, Y179, R180, Y181, and Y184) were required for the inhibitory effect of Omp25 on IFN-β induction. Altogether, our results demonstrated that Brucella Omp25 inhibits cGAS STING signaling pathway-induced IFN-β via facilitating the ubiquitin–proteasome-dependent degradation of cGAS in various mammalian monocyte/macrophages.