College of Veterinary Medicine, South China Agricultural University, Guangzhou 510651, China.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Genes (Basel). 2023 Jul 29;14(8):1555. doi: 10.3390/genes14081555.
Rabies remains a great threat to public health worldwide. So far, the mechanism of rabies virus (RABV) infection is not fully understood, and there is no effective treatment for rabies. Identifying more host restriction factors of RABV will spur the development of novel therapeutic interventions against rabies. Accumulating studies suggest that tripartite motif-containing (TRIM) proteins have great effects on virus replication. TRIMs control the antiviral responses through either direct interaction with viral proteins or indirect regulation of innate immune signaling molecules in the host. The role of TRIM25 in rabies virus (RABV) infection is poorly understood. Using next-generation sequencing, we found that TRIM25 is upregulated during HEP-Flury infection. Knockdown of TRIM25 enhances HEP-Flury production, while overexpression of TRIM25 suppresses HEP-Flury replication. Knockdown of interferon α and interferon β weakens the anti-RABV response induced by TRIM25 overexpression, and potentiates RABV production. Furthermore, we found that TRIM25 regulates type-I interferon response by targeting retinoic acid-inducible gene I (RIG-I) during HEP-Flury infection. Knockdown of RIG-I weakens the anti-HEP-Flury response induced by TRIM25 overexpression, indicating that TRIM25 regulates RABV production via the RIG-I-IFN axis. In addition, we observed that TRIM25 does not directly interact with HEP-Flury structural proteins, suggesting that TRIM25 regulates HEP-Flury production indirectly. Taken together, our work identifies TRIM25 as a new host factor involved in HEP-Flury infection, which may be a potential target for the development of antiviral drugs against RABV.
狂犬病仍然是全球公共卫生的一大威胁。到目前为止，狂犬病病毒（RABV）感染的机制尚未完全阐明，也没有有效的狂犬病治疗方法。鉴定更多 RABV 的宿主限制因子将促进针对狂犬病的新型治疗干预措施的发展。越来越多的研究表明，三结构域蛋白（TRIM）在病毒复制中具有重要作用。TRIM 通过与病毒蛋白直接相互作用或间接调节宿主中的先天免疫信号分子来控制抗病毒反应。TRIM25 在狂犬病病毒（RABV）感染中的作用知之甚少。使用下一代测序，我们发现 TRIM25 在 HEP-Flury 感染过程中上调。TRIM25 的敲低增强了 HEP-Flury 的产生，而 TRIM25 的过表达抑制了 HEP-Flury 的复制。干扰素-α和干扰素-β的敲低削弱了 TRIM25 过表达诱导的抗 RABV 反应，并增强了 RABV 的产生。此外，我们发现 TRIM25 通过在 HEP-Flury 感染过程中靶向视黄酸诱导基因 I（RIG-I）来调节 I 型干扰素反应。RIG-I 的敲低削弱了 TRIM25 过表达诱导的抗 HEP-Flury 反应，表明 TRIM25 通过 RIG-I-IFN 轴调节 RABV 的产生。此外，我们观察到 TRIM25 不会与 HEP-Flury 结构蛋白直接相互作用，这表明 TRIM25 间接调节 HEP-Flury 的产生。总之，我们的工作确定 TRIM25 是参与 HEP-Flury 感染的新宿主因子，它可能是开发抗 RABV 抗病毒药物的潜在靶点。
