Deltacoronavirus Modulates circRNA cGLIS3 Metabolism to Evade Host Antiviral Response

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.