Coronavirus Nsp15 endoribonuclease: linking viral RNA regulation to immune evasion and viral fitness.

Coronavirus nonstructural protein 15 (Nsp15) is a conserved uridine-preferring endoribonuclease (EndoU). Studies using mouse hepatitis virus (MHV), SARS-CoV-2, and other coronaviruses have shown that Nsp15 associates with replication-transcription complexes (RTCs) and contributes to viral immune evasion. Structural studies of alpha- and beta-coronavirus Nsp15 proteins reveal a hexameric enzyme that engages viral RNA substrates and cleaves at unpaired uridines through an RNase A-like, largely metal-independent mechanism stimulated by divalent cations. The Nsp15 hexamer functions as a dynamic, cooperative platform capable of accommodating extended double-stranded and structured RNA substrates. Genetic studies in several coronaviruses indicate that EndoU activity is dispensable for viral RNA synthesis in cell culture, but critical for suppressing host antiviral responses. Loss of EndoU activity promotes accumulation of immunostimulatory RNA species and activation of dsRNA-sensing pathways, including MDA5-dependent interferon signaling, PKR-mediated translational arrest, and the OAS/RNase L system. Mechanistically, Nsp15 is proposed to suppress these responses by selectively processing uridine-rich and structurally accessible regions in viral RNA, including poly(U)-containing negative-strand RNAs, and elements within untranslated regions and transcription regulatory sequences. Beyond catalysis, Nsp15 may contribute to RTC organization and regulate viral RNA recombination or defective viral genome formation, although these roles remain less well-defined and may vary among coronavirus species. Together, these findings support a model in which Nsp15 functions as a regulator of viral RNA composition and immunogenicity rather than solely as a degradative nuclease. This review summarizes recent advances in Nsp15 structure, RNA processing, immune evasion, and antiviral targeting, and highlights key unresolved questions.