Roles of the M2 protein of influenza A virus.

The matrix protein 2 (M2) is one of the most representative and widely studied ion channel proteins, which plays broad biological roles in the life cycle of the influenza A virus. The M2 protein affects the function of host cells and the regulation of cellular homeostasis in an ion channel activity-dependent or-independent manner and it is also the target for anti-influenza virus drugs, such as amantadine and rimantadine. The focus of this review is to summarize the research progress on the M2 protein, such as structure and function, vaccine and drug development as well as antagonist of host innate immune responses. A particular emphasis is placed on the multifaceted roles of M2 beyond canonical ion conduction. Specifically, M2 modulates the MAVS pathway through direct interaction with MAVS and by inducing ROS production, which amplifies interferon-mediated inflammation while paradoxically disrupting autophagic degradation of MAVS aggregation. Concurrently, the M2 protein orchestrates autophagy regulation by inhibiting autophagosome-lysosome fusion and initiating AKT-mTOR signaling, thus stabilizing the viral polymerase to enhance viral replication. A comprehensive understanding of these mechanisms is essential for advancing universal M2-based vaccine strategies and novel host-directed antiviral therapies.