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 m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and viral nucleocapsid (N) protein promote biogenesis of the m6A-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 m6A-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.