Coxsackievirus B regulates host circAKAP10 expression to promote viral replication

Abstract

Coxsackievirus B (CVB) infection is associated with severe clinical manifestations including myocarditis and encephalitis. However, the molecular mechanisms underlying viral replication remain unclear. The role of circular RNAs (circRNAs), which are known to regulate cellular processes by acting as miRNA sponges or interacting with proteins, has not been thoroughly explored in CVB pathogenesis. Here, we identified hsa_circ_0042409 (circAKAP10) as a proviral circRNA that is significantly upregulated in CVB-infected HeLa cells. Functional studies demonstrated that circAKAP10 overexpression enhanced viral replication and virion production, whereas its silencing suppressed CVB titers. Mechanistically, circAKAP10 sequesters miR-1256, which in turn derepresses the NTRK2 gene, which encodes a kinase that is critical for activation of ERK signaling. Dual-luciferase assays confirmed direct binding between circAKAP10 and miR-1256, as well as between miR-1256 and the 3'UTR of NTRK2. Inhibiting NTRK2 or ERK phosphorylation blocked the pro-replicative effects of circAKAP10. These findings delineate a novel regulatory axis (circAKAP10/miR-1256/NTRK2/ERK) that promotes CVB replication and provides a potential therapeutic target for treating enteroviral infections.