Abstract

Our previous studies have shown that major vault protein (MVP) is a virus-induced host factor that participates in the innate immune response. However, little is known about the role of MVP in Influenza A virus (IAV)- induced ferroptosis. In this study, the expression of MVP was found to positively correlate with that of interferon regulatory factor 1 (IRF1) and ferroptosis suppressor protein 1 (FSP1), but not with glutathione peroxidase 4 (GPX4), in peripheral blood mononuclear cells from patients with IAV. In vitro and in vivo evidence indicate that MVP is a potent factor in ferroptosis resistance during IAV infection. Upon investigating the mechanisms underlying this event, MVP was found to sequester IRF1 from tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby suppressing its polyubiquitination and nuclear localization. Therefore, the transcription inhibition of IRF1 on the FSP1 promoter was removed, thereby enhancing FSP1 expression. A second wave of MVP regulation for IAV-induced ferroptosis also occurs. In the presence of the MVP, transcriptionally induced FSP1 is released from IRF1, leading to its ubiquitination and myristoylation, which enable its recruitment to the plasma membrane, where it functions as an oxidoreductase. These findings define a ferroptosis suppression pathway during IAV infection.