Liu Xiaolan, Wang Hua, Yuan Mengran, Zhang Tianyi, Wang Qimeng, Chen Nuo, Zhou Xiaoxiang, He Min, Ji Zengjun, Shen Hongxing
Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, PR China; Department of Clinical Laboratory, Norinco General Hospital, Xi'an, Shaanxi 710065, PR China.
Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, PR China.
Int J Biol Macromol. 2025 May;305(Pt 2):140988. doi: 10.1016/j.ijbiomac.2025.140988. Epub 2025 Feb 15.
Enterovirus infections are implicated in the pathogenesis of inflammatory diseases, such as viral myocarditis, meningitis, and pancreatitis. These infections activate innate and inflammatory immune responses upon viral entry into host cells. However, the precise mechanisms through which enteroviruses induce inflammation to facilitate viral replication remain unclear. N(6)-methyladenosine (mA), one of the most abundant internal modifications on eukaryotic mRNAs, is regulated by METTL3, a key "writer" enzyme in the mA methyltransferase complex. This study identifies RIO kinase 3 (RIOK3), a serine-threonine protein kinase, involved in innate immunity, inflammation, and cell cycle regulation, as a critical factor in Coxsackievirus B3 (CVB3) infection. CVB3 infection significantly increases RIOK3 expression both in vivo and in vitro, accompanied by elevated m6A modifications on RIOK3 mRNA. METTL3-mediated m6A modification enhances RIOK3 transcription, which in turn downregulates CDC42, a small GTPase of the Rho subfamily, that regulates key cellular processes, including antiviral signaling. This suppression of CDC42 promotes CVB3 replication. Additionally, RIOK3 and CDC42 modulate the NF-κB signaling pathway, a pivotal regulator of inflammatory and immune responses during infection. These findings reveal that mA-modified RIOK3 promotes enterovirus replication by activating the NF-κB signaling pathway via CDC42 suppression, providing novel insights into the molecular mechanisms of enterovirus pathogenesis.
肠道病毒感染与炎症性疾病的发病机制有关，如病毒性心肌炎、脑膜炎和胰腺炎。这些感染在病毒进入宿主细胞后激活先天性和炎症性免疫反应。然而，肠道病毒诱导炎症以促进病毒复制的确切机制仍不清楚。N6-甲基腺苷（m6A）是真核生物mRNA上最丰富的内部修饰之一，由m6A甲基转移酶复合物中的关键“书写”酶METTL3调控。本研究确定了RIO激酶3（RIOK3），一种参与先天性免疫、炎症和细胞周期调控的丝氨酸-苏氨酸蛋白激酶，是柯萨奇病毒B3（CVB3）感染中的关键因子。CVB3感染在体内和体外均显著增加RIOK3的表达，同时RIOK3 mRNA上的m6A修饰升高。METTL3介导的m6A修饰增强RIOK3转录，进而下调Rho亚家族的小GTP酶CDC42，CDC42调节包括抗病毒信号在内的关键细胞过程。对CDC42的这种抑制促进了CVB3的复制。此外，RIOK3和CDC42调节NF-κB信号通路，NF-κB信号通路是感染期间炎症和免疫反应的关键调节因子。这些发现揭示，mA修饰的RIOK3通过抑制CDC42激活NF-κB信号通路促进肠道病毒复制，为肠道病毒发病机制的分子机制提供了新的见解。
