非洲猪瘟病毒I226R蛋白抑制cGAS-STING通路介导的天然免疫应答

The I226R protein of African swine fever virus inhibits the cGAS-STING-mediated innate immune response

摘要:

本研究旨在探究非洲猪瘟病毒(African swine fever virus, ASFV) I226R蛋白(I226R protein, pI226R)抑制cGAS-STING信号通路的作用机制。利用双荧光素酶报告系统和实时荧光定量PCR (real-time quantitative PCR, qPCR)证明pI226R显著抑制cGAS-STING通路介导的I型干扰素及干扰素刺激相关基因的产生。免疫共沉淀及激光共聚焦显微镜试验发现pI226R与cGAS蛋白相互作用。免疫印迹分析证明pI226R通过自噬-溶酶体途径促进cGAS蛋白的降解。同时，pI226R阻碍了cGAS与E3泛素连接酶三基序蛋白56 (tripartite motif protein 56, TRIM56)的结合，导致cGAS的单泛素化减弱，从而抑制了cGAS的活化和cGAS-STING通路的激活。总之，本研究证明ASFV pI226R通过拮抗cGAS进而抑制宿主的抗病毒天然免疫反应，进一步增加了对研究ASFV免疫逃逸机制的理解，为疫苗的研发提供了理论基础。

Abstract:

This study aimed to explore the mechanism of how African swine fever virus (ASFV) I226R protein inhibits the cGAS-STING signaling pathway. We observed that I226R protein (pI226R) significantly inhibited the cGAS-STING-mediated type I interferons and the interferon-stimulated genes production by dual-luciferase reporter assay system and real-time quantitative PCR. The results of co-immunoprecipitation assay and confocal microscopy showed that pI226R interacted with cGAS. Furthermore, pI226R promoted cGAS degradation through autophagy-lysosome pathway. Moreover, we found that pI226R decreased the binding of cGAS to E3 ligase tripartite motif protein 56 (TRIM56), resulting in the weakened monoubiquitination of cGAS, thus inhibiting the activation of cGAS and cGAS-STING signaling. In conclusion, ASFV pI226R suppresses the antiviral innate immune response by antagonizing cGAS, which contributes to an in-depth understanding of the immune escape mechanism of ASFV and provides a theoretical basis for the development of vaccines.