Deltacoronavirus Modulates circRNA <i>cGLIS3</i> Metabolism to Evade Host Antiviral Response

ABSTRACT Circular RNAs (circRNAs) are dynamically remodeled during infection, yet how viruses exploit circRNA‐RNA binding protein (RBP) circuits remains poorly understood. Here, we report a cGLIS3 ‐IGF2BP2‐linked TNF‐α regulatory axis triggered by deltacoronavirus infection to inhibit antiviral innate immunity. The host m 6 A reader insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2) and viral nucleocapsid (N) protein promote biogenesis of the m 6 A‐modified cGLIS3 by strengthening the GLIS3 exon 3 circulation. Interaction assay reveals that K‐Homology domain of IGF2BP2 or the linker region of viral protein N binds to GLIS3 pre‐mRNA to achieve cGLIS3 biogenesis, respectively. IGF2BP2 stabilizes the m 6 A‐modified cGLIS3 against RNase L‐mediated degradation. cGLIS3 attenuates IGF2BP2‐driven TNF‐α induction to facilitate deltacoronavirus replication by accelerating K48‐linked ubiquitin degradation of IGF2BP2. Together, our findings uncover a coronavirus‐elicited circRNA‐RBP crosstalk circuit to suppress innate immunity, establishing cGLIS3 as a mechanistically defined regulator of virus‐host interactions.