The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China.
School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
Virology. 2024 Dec;600:110249. doi: 10.1016/j.virol.2024.110249. Epub 2024 Sep 17.
Influenza is an acute viral respiratory infection that causes mild to severe illness in humans and animals. Current studies show that glucose-regulated protein 78 (GRP78) can exert crucial functions during viral infection; however, the mechanism by which GRP78 regulates influenza A virus (IAV) infection remains unclear. In the present study, we found that IAV infection increased GRP78 expression. Overexpression of GRP78 significantly inhibited IAV replication, as indicated by reduced viral mRNA levels, protein levels, and viral titers. Mechanistically, Type I interferon (IFN) response signaling is upregulated during IAV infection by GRP78. Further study showed that GRP78 interacts with tyrosine kinase 2 (TYK2) and enhances its phosphorylation, thereby activating downstream STAT1/2 and antiviral IFN-stimulated gene (ISG) expression. Collectively, these results demonstrate an important mechanism by which GRP78 exerts in innate antiviral effect in IAV infection. This mechanism could be used as a therapeutic target for anti-influenza treatment.
流感是一种急性病毒性呼吸道感染，可导致人类和动物轻症到重症疾病。目前的研究表明，葡萄糖调节蛋白 78（GRP78）在病毒感染过程中可以发挥关键作用；然而，GRP78 调节甲型流感病毒（IAV）感染的机制尚不清楚。在本研究中，我们发现 IAV 感染会增加 GRP78 的表达。GRP78 的过表达显著抑制了 IAV 的复制，这表现在病毒 mRNA 水平、蛋白水平和病毒滴度的降低。在机制上，GRP78 在 IAV 感染过程中上调了 I 型干扰素（IFN）反应信号。进一步的研究表明，GRP78 与酪氨酸激酶 2（TYK2）相互作用并增强其磷酸化，从而激活下游 STAT1/2 和抗病毒 IFN 刺激基因（ISG）表达。总之，这些结果表明了 GRP78 在 IAV 感染中发挥固有抗病毒作用的重要机制。该机制可作为抗流感治疗的治疗靶点。
