State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 10049, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China.
Fish Shellfish Immunol. 2019 Jul;90:180-187. doi: 10.1016/j.fsi.2019.04.297. Epub 2019 Apr 29.
In mammals and fish, emerging evidence highlights that TRIM family members play important roles in the interferon (IFN) antiviral immune response. Fish TRIM family has undergone an unprecedented expansion leading to generation of finTRIM subfamily, which is exclusively specific to fish. Our recent results have shown that FTRCA1 (finTRIM C. auratus 1) is likely a fish species-specific finTRIM member in crucian carp C. auratus and acts as a negative modulator to downregulate fish IFN response by autophage-lysosomal degradation of protein kinase TBK1. In the present study, we found that FTRCA1 also impedes the activation of crucian carp IFN promoter by IRF7 but not by IRF3. Mechanistically, FTRCA1 attenuates IRF7 transcription levels likely due to enhanced decay of IRF7 mRNA, leading to reduced IRF7 protein levels and subsequently reduced fish IFN expression. E3 ligase activity is required for FTRCA1 to negatively regulate IRF7-mediated IFN response, because ligase-inactive mutants and the RING-deleted mutant of FTRCA1 lose the ability to block the activation of crucian carp IFN promoter by IRF7. These results together indicate that FTRCA1 is a multifaceted modulator to target different signaling factors for shaping fish IFN response in crucian carp.
在哺乳动物和鱼类中，新出现的证据强调了 TRIM 家族成员在干扰素（IFN）抗病毒免疫反应中发挥重要作用。鱼类 TRIM 家族经历了前所未有的扩张，导致 finTRIM 亚家族的产生，该亚家族专门存在于鱼类中。我们最近的研究结果表明，FTRCA1（finTRIM C. auratus 1）可能是鲤鱼 C. auratus 中鱼类特异性的 finTRIM 成员，通过蛋白激酶 TBK1 的自噬溶酶体降解来负调控鱼类 IFN 反应。在本研究中，我们发现 FTRCA1 也能抑制 IRF7 但不能抑制 IRF3 激活鲤鱼 IFN 启动子。从机制上讲，FTRCA1 可能通过增强 IRF7 mRNA 的降解来降低 IRF7 转录水平，从而导致 IRF7 蛋白水平降低，进而降低鱼类 IFN 的表达。E3 连接酶活性对于 FTRCA1 负调控 IRF7 介导的 IFN 反应是必需的，因为连接酶失活突变体和 FTRCA1 的 RING 缺失突变体丧失了阻断 IRF7 激活鲤鱼 IFN 启动子的能力。这些结果共同表明，FTRCA1 是一种多效调节剂，可针对不同的信号因子，在鲤鱼中塑造 IFN 反应。
