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 autophagosome accumulation, the mechanisms regulating M2 stability remain incompletely understood. Our previous work established that IAV inhibits SERCA activity to trigger autophagosome accumulation. Here, we identify c-Fos as a critical downstream mediator that stabilizes M2, thereby promoting both autophagosome accumulation and viral replication. Mechanistically, IAV infection drives M2-dependent cytosolic calcium elevation, which upregulates c-Fos expression. The induced c-Fos then binds to M2, protecting it from proteasomal and lysosomal degradation and thereby increasing M2 abundance. This stabilized M2 not only directly enhances viral replication but also sustains autophagosome accumulation to further augment viral growth. Collectively, our findings establish c-Fos as a key regulator of IAV replication via M2 stabilization, revealing a novel mechanism by which the virus amplifies its propagation. These interactions represent potential therapeutic targets for antiviral intervention. IMPORTANCE Influenza 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 self-reinforcing mechanism in which IAV exploits the host transcription factor c-Fos to stabilize its own M2 protein, thereby enhancing viral 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.