c-Fos enhances influenza virus replication by stabilizing the M2 protein and promoting autophagosome accumulation

Abstract

The influenza A virus (IAV) employs multiple strategies to hijack host cellular machinery for efficient replication. While autophagosome accumulation is known to promote IAV replication, and the viral matrix protein 2 (M2) ion channel protein plays essential roles in viral uncoating, assembly, and autophagy induction, the mechanisms regulating M2 stability remain incompletely understood. Furthermore, although c-Fos participates in the replication of various viruses, its function in IAV infection has not been characterized. Here, we identify c-Fos as a critical proviral host factor that enhances IAV replication through stabilizing M2 protein and promoting autophagosome accumulation. We demonstrate that IAV infection triggers M2-mediated cytosolic calcium elevation, which upregulates c-Fos expression. The induced c-Fos physically interacts with M2 and prevents its proteasome and lysosomal degradation, thereby increasing M2 accumulation. This stabilized M2 protein as a viral protein directly facilitates viral replication while simultaneously promoting autophagosome accumulation to further enhance the process. Our findings reveal a novel positive feedback loop in IAV infection, establishing c-Fos as a key regulator of IAV replication through M2 stabilization, and highlighting these interactions as potential therapeutic targets for antiviral intervention. IMPORTANCEInfluenza A virus (IAV) remains a significant global health threat, causing substantial morbidity and mortality. Understanding virus-host interactions is crucial for developing antiviral strategies. Here, we uncover a previously unrecognized positive feedback loop in which IAV exploits the host transcription factor c-Fos to enhance its own replication. We demonstrate that IAV infection upregulates c-Fos through M2-mediated calcium signaling, and the induced c-Fos in turn stabilizes the viral M2 protein. This stabilized M2 not only directly supports viral replication but also promotes autophagosome accumulation, further facilitating virus production. Our findings establish c-Fos as a critical proviral host factor and reveal a mechanism by which IAV hijacks host cellular machinery to create a favorable environment for efficient replication. The identification of this c-Fos-M2 axis not only advances our understanding of IAV-host interactions but also opens new avenues for therapeutic intervention targeting this vulnerability in the viral life cycle.