Influenza A virus nonstructural protein 2 inhibits IFN-I signaling via competing with MAVS to bind to UBL7

Influenza A virus (IAV) utilizes multiple strategies to antagonize type I interferon (IFN-I)-mediated antiviral responses to enhance its propagation within the host. Nonstructural protein 2 (NS2) is a component of the viral particle participating in the nuclear export of viral ribonucleoprotein complexes (vRNPs). However, the role of NS2 in antiviral immune evasion is still poorly understood. Here, we report that NS2 suppresses IFN-I responses by interacting with ubiquitin like 7 (UBL7, also known as BMSC-UbP), a positive regulator of IFN-I signaling that promotes K27-linked polyubiquitination of MAVS. NS2 reduces the K27-linked polyubiquitination of MAVS by interacting with UBL7, thereby hindering the UBL7-MAVS interaction, resulting in suppressed activation of IFN-I signaling. Knockdown of NS2 during IAV (PR8, H1N1) enhances IFN-I signaling in UBL7 overexpressing cells and wild-type mouse embryonic fibroblasts (MEFs), but not in UBL7 knockout (UBL7 KO) MEFs. Taken together, our findings identify a novel NS2-mediated immune evasion mechanism during IAV infection, in which NS2 antagonizes UBL7-dependent activation of MAVS signaling, thereby suppressing type I interferon responses. These findings provide new insights into the interplay between IAV and the host innate immune response.