青鱼SIKE在TBK1介导的先天免疫信号途径中的功能探究

先天免疫系统是鱼类等低等脊椎动物抵抗外界不利因素的主要防御系统，TBK1在先天免疫系统中承接着多种信号通路的传递过程，对其活性的精确调节在维持细胞内稳态方面有着非常重要的作用。在哺乳动物中，SIKE是TBK1的抑制因子之一，项目申请人首次报道了鱼类中SIKE的存在，并初步证明青鱼SIKE参与了先天免疫系统的调节过程。前期研究中我们发现，SIKE能够负调节RLR信号通路中主要蛋白对下游干扰素的诱导能力，并且在自然状态下能够与TBK1结合，但是其调节TBK1的具体机制还不明确。我们推测SIKE与TBK1结合后通过磷酸化修饰影响TBK1发挥正常生理功能进而调节先天免疫系统。为证实这一推测，我们采用CRISPR-Cas9基因编辑技术以及串联质谱技术，探究SIKE影响TBK1参与的先天免疫信号途径的具体机制。本课题将为了解SIKE的功能提供基础，为全面了解鱼类先天免疫系统提供参考。

The innate immune system is the main defense system against adverse external factors in lower vertebrates such as fish. TBK1 participates in the transmission process of various signaling pathways in the innate immune system, and plays a very important role in maintaining homeostasis of cells by precisely regulating its activity.SIKE is one of the inhibitors of TBK1 in mammals. We first reported the presence of SIKE in fish and preliminarily demonstrated that SIKE is involved in the regulation of the innate immune system of black carp.In previous studies, we found that SIKE can negatively regulate the induction capacity of major proteins in the RLR signaling pathway to the downstream interferon, and can bind to TBK1 in the natural state, but the specific mechanism of its regulation of TBK1 remains unclear.We speculate that the combination of SIKE and TBK1 may affect the normal physiological function of TBK1 to regulate the innate immune system through phosphorylation.To confirm this hypothesis, we use CRISPR-Cas9 gene editing and tandem mass spectrometry to explore the specific mechanism by which SIKE affects the innate immune signaling process in which TBK1 is involved.This study will provide a basis for understanding the function of SIKE and a reference for a more comprehensive understanding of the innate immune system of fish.