WDFY1在TLRs信号转导通路中的作用及其分子机制

TLRs signaling plays critical roles in innate immunity against pathogens. TLRs,located on cell membrane or endosomes, initiate MyD88- or TRIF- dependent signal transductions after recoginizing pathogenic conserved structures. TLRs signaling activates several transcriptional factors, including NFkappaB,AP-1 and IRFs,and finally leads to inflammation or type I interferon effects to fight against pathogens. Researches on subtle regulation of TLRs signalings are hotspots of innate immunity all the time. In order to identify new molecules in regulating TLR signalings, we have performed luciferase reporter assays, and identified a new molecule, called WDFY1, which can enhance polyI:C-triggered activation of interferon beta promoter.We also found WDFY1 enhanced LPS-triggered activation of interferon beta promoter and enhancer. These results strongly suggest that WDFY1 participates in positive regulation of TLR3- and TLR4- signalings. In this project, we will further confirm the roles of WDFY1 in TLR signalings and figure out the mechanism in details. The research will replenish the theory of TLR signaling, and provide new clues for developing effective drugs.

TLRs信号转导通路在抵御病原体入侵的天然免疫效应中发挥重要作用。位于细胞膜或内体上的TLRs识别病原体保守结构后，通过依赖MyD88或者TRIF的信号转导通路活化NFkappaB，AP-1和IRF3在内的一系列转录因子，启动炎症效应和I型干扰素效应。TLRs信号转导通路的精细调控机制的研究一直是天然免疫领域的研究热点之一。我们利用荧光素酶报告基因系统筛选出了一个能协同polyI:C诱导I型干扰素表达的分子WDFY1。前期实验表明：WDFY1剂量依赖性地协同polyI:C或LPS诱导IFN-beta启动子和增强子的活化以及抗病毒蛋白的转录，提示WDFY1参与TLR3和TLR4信号转导通路的调控。本项目将进一步确定WDFY1的功能，并深入探讨其作用机制，以充实TLRs信号转导的调控机制，为寻求有效的药物干预靶点提供线索。

项目围绕天然免疫领域干扰素产生的调控机制开展了深入研究，筛选出能协同病毒模拟物诱导I型干扰素表达的分子WDFY1，并进一步发现WDFY1是识别病毒双链RNA的TLR3、识别细菌脂多糖的TLR4信号转导通路中的重要接头分子，可以辅助位于细胞内体上的TLR3/TLR4招募下游分子TRIF，促进TRIF组建信号复合体，从而促进TLR3、TLR4介导的抗病毒抗细菌天然免疫反应；发现干扰素下游基因产物IFITM3负调控RNA病毒感染诱导的I型干扰素信号通路，其分子机制是受IFN诱导而大量产生的IFITM3除了发挥抑制病毒的作用之外，还可以增加自噬体体积，并将与之相互作用的胞质内IRF3拉入自噬体，促进IRF3的自噬降解，从而抑制信号通路持续激活。相关研究成果分别发表在EMBO Reports和Cell Mol Immunol上，其中WDFY1的文章被列为同期杂志的热点论文，并被著名丹麦免疫学家Søren Paludan在同期杂志上点评为TLRs通路的重要发现。项目的研究成果为抗感染天然免疫的分子机制做出了贡献，也为后续研究打下了基础。