猪IFIT3蛋白正向调控I型干扰素介导的JAK-STAT信号通路的分子机制研究

Type I interferon (IFN) exert antiviral effect through triggering the JAK-STAT signaling pathway to inducing expression of IFN-induced genes. IFIT3 is an early discovered IFN-induced gene, with a variety of functions such as antiviral and immune-regulation. Our previous study indicated that porcine IFIT3 (poIFIT3) can positively regulate type I IFN-mediated JAK-STAT signaling pathway, but the specific mechanism remains unclear. Based on above findings, we will firstly determine the signal molecules targeted by poIFIT3 in JAK-STAT pathway. Then, we will reveal the molecular strategies of poIFIT3 in regulating JAK-STAT pathway. Finally we will identify the key domains of poIFIT3 involved in regulating JAK-STAT pathway. This study aims to clarify the molecular mechanism on that poIFIT3 positively regulate type I IFN-mediated JAK-STAT pathway, which laid the foundation for the further understanding the antiviral and immune-regulation functions of IFIT3.

I型干扰素（Interferons, IFN）通过活化下游JAK-STAT信号通路引起IFN诱导基因的表达，从而发挥抗病毒效应。IFIT3是较早被发现的IFN诱导基因，具有抗病毒和免疫调控等功能。前期研究揭示猪IFIT3（poIFIT3）能够正向调节I型IFN介导的JAK-STAT信号通路，但具体机制尚不清楚。本研究以此为切入点，首先明确poIFIT3在JAK-STAT通路中靶向的信号分子；其次揭示poIFIT3调控JAK-STAT通路的分子策略；最后鉴定poIFIT3发挥调控作用的关键结构域。本研究旨在阐明IFIT3正向调控I型IFN介导的JAK-STAT通路的分子机制，为深入理解IFIT3的抗病毒和免疫调控功能奠定基础。

I型干扰素（Interferons, IFN）通过活化下游JAK-STAT信号通路引起IFN诱导基因的表达，从而发挥抗病毒效应。猪IFIT3是较早被发现的IFN诱导基因，具有抗病毒和免疫调控等功能。前期研究我们发现猪IFIT3能够正向调节I型IFN介导的JAK-STAT信号通路，但具体机制尚不清楚。基于此，我们构建了IFIT3基因敲除和过表达细胞系，证实IFIT3能够促进STAT1、STAT2和IRF9表达以及增强IFNa诱导的ISRE活化，从而增强对伪狂犬病毒等病毒的抗病毒应答。进一步研究发现IFIT3能够利用N端结构域与STAT1互作以及通过C端结构域与STAT2互作，从而增强I型IFN诱导抗病毒应答。本研究发现了IFIT3新的互作蛋白，并揭示IFIT3正向调控I型IFN介导的JAK-STATs通路的分子机制，为深入理解IFIT3的抗病毒和免疫调控功能奠定了基础。