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

Enterovirus 2B is a highly conserved, functionally versatile, nonstructural protein. The classic viroporin model, which restricts its role to ion channel formation, cannot account for its interactions with host factors such as Bcl-2-associated X protein, interleukin enhancer-binding factor 2, and karyopherin subunit alpha 1, nor its functional divergence among enteroviruses. We propose a novel, testable membrane stress sensor hypothesis: the transmembrane helices of 2B sense lipid composition and pH changes, and through conformational dynamics, spatiotemporally coordinate calcium signaling, cell death pathway selection, including apoptosis, pyroptosis, autophagy, and ferroptosis, and immune evasion. We elaborate on this framework across six dimensions: structure-function mapping, calcium signaling, cell death pathways, immune evasion, evolutionary footprint, and antiviral targeting, along with cross-virus comparisons. We highlight key evidence gaps and limitations, and propose several future research directions. This framework establishes a mechanistic foundation for understanding 2B function and guiding rational anti-enteroviral drug designs.