Enterovirus 2B protein: From viroporin to membrane stress sensor, mechanistic principles of multi-pathway regulation.

Enterovirus 2B functions as a membrane stress sensor coordinating multiple cell death pathways, not just as a viroporin, with conformational dynamics linked to calcium signaling and immune evasion.

• Why it matters: Understanding 2B's diverse roles is crucial because its interactions with host factors and functional divergence among enteroviruses are not explained by the traditional viroporin model, limiting antiviral strategies.
• What they did: The authors propose a novel membrane stress sensor hypothesis based on the transmembrane helices of 2B sensing lipid composition and pH changes, influencing calcium signaling, cell death pathways, and immune evasion, supported by a six-dimensional framework.
• The result: This mechanistic framework advances understanding of 2B's multifunctionality and provides a foundation for designing targeted anti-enteroviral drugs, addressing key evidence gaps and future research directions.