TRIM2 negatively regulates antiviral immunity by degradation of MDA5 and STAT2 during influenza A virus infection

Abstract This study identifies TRIM2 as an interferon-stimulated gene (ISG) regulated by both type I and type II interferons. Contrary to the typical antiviral role of most ISGs, TRIM2 significantly enhances influenza A virus (IAV) replication both in vitro and in vivo. Mechanistically, TRIM2 functions as a negative regulator of the MDA5-mediated antiviral signaling pathway, contributing to the suppression of IFN-β production in part through promoting K48-linked polyubiquitination of MDA5. It directly interacts with MDA5 via its CC and Fn domains, promoting K48-linked polyubiquitination of MDA5 at Lysine 538, which leads to its proteasomal degradation and subsequent suppression of IFN-β production. Furthermore, TRIM2 interacts with and degrades STAT2 via K48-linked ubiquitination, further suppressing interferon signaling. In vivo experiments demonstrated that TRIM2 deficiency modulates the host response to IAV infection, leading to reduced viral load, attenuated lung injury, and improved survival outcomes. These findings reveal TRIM2 as a novel and unconventional ISG that functions as a negative regulator of the host antiviral response, positioning it as a potential therapeutic target for combating IAV infection.