MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
Virol Sin. 2021 Dec;36(6):1503-1519. doi: 10.1007/s12250-021-00442-3. Epub 2021 Sep 6.
Japanese encephalitis virus (JEV) is a flavivirus transmitted by mosquitoes that causes severe encephalitis in humans and animals. It has been suggested that AXL, a transmembrane protein, can promote the replication of various flaviviruses, such as dengue (DENV), Zika (ZIKV), and West Nile (WNV) viruses. However, the effect of AXL on JEV infection has not yet been determined. In the present study, we demonstrate that AXL is down-regulated after JEV infection in the late stage. JEV NS2B-3 protein specifically interacted with AXL, and promoted AXL degradation through the ubiquitin-proteasome pathway. AXL-degradation increased cell apoptosis by disrupting phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction. In addition, the degradation of AXL promoted JEV release to supernatant, whereas the virus in the cell lysates decreased. The supplementation of AXL ligand Gas6 inhibited the JEV-mediated degradation of AXL. Altogether, we discover a new function of NS2B-3 during the process of JEV replication, and provide a new insight into the interactions between JEV and cell hosts.
日本脑炎病毒（JEV）是一种由蚊子传播的黄病毒，可导致人类和动物罹患严重脑炎。已有研究表明，跨膜蛋白 AXL 可促进多种黄病毒（如登革热病毒（DENV）、寨卡病毒（ZIKV）和西尼罗河病毒（WNV））的复制。然而，AXL 对 JEV 感染的影响尚未确定。在本研究中，我们发现 JEV 感染后晚期 AXL 下调。JEV NS2B-3 蛋白特异性与 AXL 相互作用，并通过泛素-蛋白酶体途径促进 AXL 降解。AXL 降解通过破坏磷脂酰肌醇 3-激酶（PI3K）/Akt 信号转导增加细胞凋亡。此外，AXL 的降解促进了 JEV 向上清液的释放，而细胞裂解物中的病毒减少。AXL 配体 Gas6 的补充抑制了 JEV 介导的 AXL 降解。总之，我们发现了 NS2B-3 在 JEV 复制过程中的一个新功能，为 JEV 与宿主细胞之间的相互作用提供了新的见解。
