Ceftazidime reduces cellular Skp2 to promote type‐I interferon activity

Abstract Skp2 plays multiple roles in malignant tumours. Here, we revealed that Skp2 negatively regulates type‐I interferon (IFN‐I)‐mediated antiviral activity. We first noticed that Skp2 can promote virus infection in cells. Further studies demonstrated that Skp2 interacts with IFN‐I receptor 2 (IFNAR2) and promotes K48‐linked polyubiquitination of IFNAR2, which accelerates the degradation of IFNAR2 proteins. Skp2‐mediated downregulation of IFNAR2 levels inhibits IFN‐I signalling and IFN‐I‐induced antiviral activity. In addition, we uncovered for the first time that the antibiotic ceftazidime can act as a repressor of Skp2. Ceftazidime reduces cellular Skp2 levels, thus enhancing IFNAR2 stability and IFN‐I antiviral activity. This study reveals a new role of Skp2 in regulating IFN‐I signalling and IFN‐I antiviral activity and reports the antibiotic ceftazidime as a potential repressor of Skp2.