LAUSR

Significance Coronaviruses can expertly evade our immune system. One way they do this is by employing the viral protein nsp15. This protein contains an endoribonuclease domain (EndoU), which cleaves viral RNA that would otherwise alert the cell that an infection has begun. The catalytic site of nsp15 has been difficult to target with antivirals. We made coronavirus nsp15 mutant viruses and identified the amino-terminal domain to be equally essential for EndoU function. We found that EndoU evades several host sensors, including Z-form nucleic acid-binding protein 1 (ZBP1), to dampen a protective host interferon response and delay cell death. This allows coronaviruses to replicate to high levels and cause disease. This work identifies a potential target for the development of nsp15 antivirals.