Lv Xueying, Zheng Tian, Lei Xiaobo, Ren Lili, Zhao Shiyi, Wang Jingfeng, Zhuo Zhou, Wang Jianwei
NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, China; State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China; Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, China.
NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, China.
Virology. 2025 Feb;603:110397. doi: 10.1016/j.virol.2025.110397. Epub 2025 Jan 7.
The influenza A virus evades the host innate immune response to establish infection by inhibiting RIG-I activation through its nonstructural protein 1 (NS1). Here, we reported that receptor-transporting protein 4 (RTP4), an interferon-stimulated gene (ISG), targets NS1 to inhibit influenza A virus infection. Depletion of RTP4 significantly increased influenza A virus multiplication, while NS1-deficient viruses were unaffected. Mechanistically, RTP4 interacts with NS1 in an RNA-dependent manner and sequesters it from the TRIM25-RIG-I complex, thereby restoring TRIM25-mediated RIG-I K63-linked ubiquitination and subsequent activation of IRF3. Antiviral activity of RTP4 requires the evolutionarily conserved CXXC motifs and an H149 residue in the zinc finger domain, mutations of which disrupted RTP4-NS1 interaction and abrogated the ability of RTP4 to rescue RIG-I-mediated signaling. Collectively, our findings provided insights into the mechanism by which an ISG restricts influenza A virus replication by reactivating host antiviral signaling.
甲型流感病毒通过其非结构蛋白1（NS1）抑制RIG-I激活来逃避宿主先天免疫反应以建立感染。在此，我们报道了受体转运蛋白4（RTP4），一种干扰素刺激基因（ISG），靶向NS1以抑制甲型流感病毒感染。RTP4的缺失显著增加了甲型流感病毒的增殖，而缺乏NS1的病毒则不受影响。从机制上讲，RTP4以RNA依赖的方式与NS1相互作用，并将其从TRIM25-RIG-I复合物中隔离出来，从而恢复TRIM25介导的RIG-I K63连接的泛素化以及随后IRF3的激活。RTP4的抗病毒活性需要进化上保守的CXXC基序和锌指结构域中的H149残基，这些位点的突变破坏了RTP4与NS1的相互作用，并消除了RTP4拯救RIG-I介导的信号传导的能力。总的来说，我们的研究结果为ISG通过重新激活宿主抗病毒信号来限制甲型流感病毒复制的机制提供了见解。
