Coronavirus evades antiviral innate immune responses through encoding multiple viral proteins, thereby facilitating viral replication. However, little is known whether different coronaviruses employ conserved proteins to universally regulate innate immunity. In this study, we found that the conserved endoribonuclease NSP15 significantly suppressed type Ι interferon response, and promotes coronavirus replication. Mechanistically, NSP15 proteins from different coronaviruses interacted with IκB kinase epsilon (IKKε), a key regulator innate immunity, and wrecked the formation of liquid-liquid phase-separated (LLPS) IKKε bodies, resulting in the degradation of IKKε and a highly impaired interferon response.