Siglec-1负向调控机体抗病毒天然免疫应答的作用和机制研究

Viral infection-induced activation of RIG-I signaling and production of type I IFN play critical roles in host antiviral innate immune response, and regulation of RIG-I signaling and the corresponding mechanisms are important topics in Immunology research frontiers. Currently, the roles of Siglec family members in the regulation of immune response have attracted much attention, as they are mainly expressed in the membrane of immune cells. As we have previously reported the roles of Siglec-G in RIG-I signaling regulation (Cell, 2013; 152: 467-78) and found that activation of RIG-I signaling significantly enhanced Siglec-1 expression, we intend to focus on the roles of Siglec-1 in the regulation of RIG-I signaling in the current study because they are unknown up to now. In Siglec-1 deficient mouse, VSV infection-induced type I IFN production are enhanced while viral replication and the related death are inhibited, suggesting that Siglec-1 feedback negatively regulates RIG-I signaling and type I IFN production. Mechanistical research reveals that viral infection-induced Siglec-1 can mediate the proteasomal degradation of TBK1 to repress type I IFN production. Hence, we intend to study the detailed roles of Siglec-1 in the regulation of host antiviral innate immune response, hoping to suggest new therapeutic targets for the intervention of viral infection and the corresponding diseases.

RIG-I信号通路的活化及其介导的I型干扰素表达在机体抗病毒天然免疫应答中发挥关键作用，其信号通路的调控机制是免疫学重大和前沿科学问题。Siglec家族分子主要表达于免疫细胞膜表面，其在天然免疫信号通路中的调控作用目前受广泛关注。我们前期报道了Siglec-G调控RIG-I信号的作用和机制(Cell,2013;152:467-78），并同时发现Siglec-1在RIG-I信号活化后表达增高，而Siglec-1在RIG-I信号中的作用和机制目前未知。我们发现在Siglec-1缺陷小鼠中VSV感染促发的I型干扰素表达增高，并导致病毒复制和小鼠死亡明显减少。机制研究揭示Siglec-1可介导下游TBK1的降解进而负向调控干扰素产生。据此，我们拟研究Siglec-1调控机体抗病毒天然免疫应答的作用和具体分子机制，为干预病毒感染和治疗病毒感染性疾病提供新思路。

本研究探讨了Siglec1负向调控机体抗病毒天然免疫应答RIG-I信号通路的作用和相应的分子机制。病毒感染能够显著诱导Siglec1表达增高，并且Siglec1能够负向调控I型干扰素的表达，进而提出Siglec1是抗病毒天然免疫应答和I型干扰素表达重要的负向调控分子。此外，机制研究发现，Siglec1能够结合下游DAP12和SHP2等接头分子，进而活化E3泛素酶Trim27，从而介导了TBK1的K48位泛素化降解，从而抑制I型干扰素的表达。至此，我们提出的Siglec1调控I型干扰素表达的新机制。相关论文项目负责人以共同第一作者发表于Cell Research 2015，影响因子15.6分。在病毒感染过程中，Siglec1表达增高的机制目前未知。我们研究发现，VSV感染天然免疫细胞的过程中，miR-27a的表达显著降低，而Siglec1和Trim27均在此被证明是miR-27a的靶分子。此外，高表达miR-27a能够降低Siglec1和Trim27的表达，进而活化I型干扰素的表达。我们也构建了miR-27a的Sponge转基因小鼠，构建了miR-27a的体内敲减小鼠模型。在此小鼠模型中，天然免疫细胞Siglec1和Trim27表达显著增高，病毒感染所诱导的I型干扰素表达显著降低，病毒复制显著增加，从而在体内证明了miR-27a调控机体抗病毒天然免疫应答的作用，以及靶向抑制Siglec1和Trim27表达的机制。相关论文项目负责人以共同通讯作者发表于J. Immunol 2016，影响因子4.9分。本系列工作均由项目负责人侯晋所承担的NSFC 31370864项目资助，并在所发表文章中明确标注本工作受NSFC 31370864项目资助。本系列工作目前培养博士生4名，参加国际国内会议并作大会报告3次，体现了本系列研究具备一定的学术影响。

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