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PRRs激活的调控机制，特别是核酸传感器，以及相关的信号通路，导致细胞因子/趋化因子基因在先天性免疫反应中的诱导，以抵御病毒感染和癌症。首先，我们发现，聚腺苷二磷酸核糖聚合酶(PARP)-13短链异构体(ZAPS)通过ZAPS与RIG-I的物理结合，在RIG-I介导的人类细胞中发挥重要的干扰素刺激作用。接下来，我们揭示了ZAPS是流感病毒NS1蛋白针对病毒先天免疫逃避的一个因子。此外，我们还发现PARP-7/TIPARP和PARP-12可能是RIG-I冥想的天然免疫信号的负调节因子。此外，我们还鉴定了人巨细胞病毒(HCMV)的候选DNA传感器。另一方面，该项目对这项研究做出了贡献，其中显示了一种新的机制，即在肿瘤浸润性树突状细胞中抑制肿瘤来源DNA介导的天然免疫信号。这些结果可能为控制病毒感染和癌症提供治疗和预防方面的见解。

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.