Molecular mechanisms for the detection of microbes and cancer cells in innate immunity

在这个项目中，我们试图阐明PRR，特别是核酸传感器的激活的调节机制，以及相关的信号传导途径，导致诱导细胞因子/趋化因子基因的先天免疫反应，以抵御病毒感染和癌症。首先，我们发现聚（ADP-核糖）聚合酶（PARP）-13较短同种型（ZAPS）通过ZAPS与RIG-I的物理缔合，在由RIG-I介导的人细胞中作为IFN应答的有效刺激物起关键作用。接下来，我们揭示了ZAPS是流感病毒NS 1蛋白针对病毒先天免疫逃避的因子。此外，我们显示PARP-7/TIPARP和PARP-12作为RIG-I介导的先天免疫信号传导的可能负调节剂的作用。此外，我们还确定了一个候选的人巨细胞病毒（HCMV）的DNA传感器。另一方面，该项目对研究做出了贡献，其中已经显示出抑制肿瘤浸润树突细胞中肿瘤衍生DNA介导的先天免疫信号传导的新机制。这些结果可能为控制病毒感染和癌症提供治疗和预防见解。

In this project, we tried to elucidate a regulatory mechanism for the activation of PRRs, particularly nucleic acid sensors, and the related signaling pathways, leading to the induction of cytokine/chemokine genes in innate immune responses for host defense against viral infection and cancer. First, we found that the poly(ADP-ribose) polymerase (PARP)-13 shorter isoform (ZAPS) critically functions as a potent stimulator of IFN responses in human cells mediated by RIG-I, through the physical association of ZAPS with RIG-I. Next, we revealed that ZAPS is a factor targeted by Influenza viral NS1 protein for viral innate immune evasion. In addition, we showed a role of PARP-7/TIPARP and PARP-12 as a possible negative regulator of RIG-I-meditated innate immune signalings. Furthermore, we also identified a candidate DNA sensor for human cytomegalovirus (HCMV). On the other hand, this project contributed to the research, wherein it has been shown a novel mechanism for the suppression of innate immune signalings mediated by tumor-derived DNA in tumor-infiltrating dendritic cells. These results may provide a therapeutic and preventive insight for the control of viral infection and cancer.