蛋白激酶Riok3对病毒感染激活的Ⅰ型干扰素信号通路的调控作用及分子机制研究

Viral infectious diseases pose a long-term and serious threat to human health. It is of great significance to study and understand the regulation of host antiviral immune response. The functional study of kinase Riok3 is limited to its role in promoting the occurrence and development of various tumors, but its specific role and the underlying mechanism in the host innate immune response are still unclear. Our previous studies found that: 1) Riok3 deficiency specifically inhibits RNA virus replication in vivo and in vitro; 2) Riok3 negatively regulates the release of type I interferon and inflammatory factors activated by RNA virus and the phosphorylation of TBK1, IRF3 and NF-kappa B in RIG-I/MDA5 pathway; 3)Riok3 interacts with both RIG-I and MDA5. We speculate that Riok3 may lead ubiquitination degradation of RIG-I and MDA5 by regulating the ubiquitination process, thereby negatively regulating the type I interferon signaling pathway. On this basis, we intend to systematically reveal the regulatory role of Riok3 in the natural immune response by using myeloid-specific Riok3 knockout mice and multiple pattern recognition receptor agonists, and further elucidate its molecular mechanism. The completion of this project will reveal the new function of Riok3 in the field of innate immunity, and provide new theoretical basis and new targets for drug development of viral infectious diseases.

病毒感染性疾病长期、严重威胁人类健康，研究并深入理解宿主抗病毒免疫应答调控具有重要意义。蛋白激酶Riok3的功能研究有限，其在天然免疫应答中的具体调控作用及分子机制均未明确。我们前期研究发现：1）Riok3缺失特异性抑制RNA病毒体内、外复制；2）Riok3负向调控RNA病毒激活的Ⅰ型干扰素释放及RIG-I/MDA5通路中TBK1、IRF3和NF-κB的磷酸化；3）Riok3同时结合RIG-I和MDA5。因此，我们推测：Riok3可能通过调控泛素化过程引起RIG-I与MDA5泛素化降解，从而负向调控Ⅰ型干扰素信号通路。本项目拟在此基础上利用髓系细胞系Riok3特异性敲除小鼠及多种模式识别受体化合物激动剂，系统揭示Riok3对抗病毒天然免疫应答的调控作用，并深入阐明其具体分子机制。该项目的完成将揭示Riok3在固有免疫领域的新功能，并为针对病毒感染性疾病的药物开发提供新的理论依据和新靶点。

病毒感染性疾病长期、严重威胁人类健康，研究并深入理解宿主抗病毒免疫应答调控具有重要意义。蛋白激酶Riok3的功能研究有限，其在天然免疫应答中的具体调控作用及分子机制均未明确。本项目通过系统性研究Riok3在体、内外对多种病毒复制的影响，系统性阐明了Riok3选择性地负向调控RNA病毒激活的Ⅰ型干扰素通路从而抑制RNA病毒体内外的复制，并通过一系列分子生物学手段揭示了Riok3通过招募E3泛素化连接酶TRIM40而引起RIG-I与MDA5泛素化降解，从而负向调控Ⅰ型干扰素信号通路的分子机制。该项目的完成揭示了Riok3在固有免疫领域的新功能，并为针对病毒感染性疾病的药物开发提供了新的理论依据和新靶点。