The antiviral molecule Mx1 positively regulates the induction of type I IFN in response to influenza infection

Abstract Myxovirus resistance 1 (Mx1), a member of the dynamin-like GTPase family, has been long described to have an important function as a cell-intrinsic mechanism with broad antiviral activity against a wide range of viruses. How Mx1 imparts its antiviral activity, however, has been elusive and remains unknown. In this study we seek to understand the mechanism by which Mx1 inhibits Influenza A virus (IAV) infection in vitro. Here we found knock-down of Mx1 expression in A549 cells led to a significant reduction in the expression of interferon-stimulated genes (ISGs) following infection with IAV, along with increased viral replication. This observation is corroborated by decreased phosphorylation of interferon regulatory factor 3 (IRF3), a key transcription factor in the transcription of the ISGs, in cells depleted of Mx1. Though Mx1 is itself an ISG and its expression is upregulated in response to IFN receptor signaling, we found that it is present basally at low levels. A significant pool of Mx1 was found in the mitochondrial fraction in experiments examining its localization within the cell. Furthermore, immunoprecipitation of Mx1 in resting cells followed by mass spectrometry to investigate its potential interactions revealed a number of proteins known to be localized to the mitochondrial membrane, a location known to be an important platform for MAVS-dependent initiation of the interferon response to RNA viruses. These data taken together suggests a potential cooperative role for Mx1 in the recognition and initiation of the antiviral program during IAV infection.