Decoding the molecular cues regulating the transition of Influenza virus polymerase from transcriptase to replicase.

A conserved PB2 salt bridge between Mid-E282 and NLS-K752 stabilizes the replication-competent FluPol conformation, while PB2 residue 627 charge (E or K) governs ANP32 engagement and replication activity.

• Why it matters: The transcription–replication balance of influenza depends on FluPol switching conformations, but how PB2 interdomain contacts coordinate this transition remained unclear.
• What they did: The study mapped PB2 interdomain interactions controlling replication-competent stability, showing Mid-E282/NLS-K752 salt-bridge effects and that residue 627 charge dictates ANP32 engagement; bat influenza A viruses H17N10 and H18N11 carry serine substitutions at both sites.
• The result: Bat H17N10/H18N11 serine substitutions at E282 and K752 and at K627 impair polymerase dimerization, ANP32 interaction, and vRNA/cRNA replication; introducing E282S/K627S into human H1N1 polymerase yields phosphorylation at both positions in human cells, suggesting phosphorylation can partially compensate via a phosphomimetic adaptation mechanism.

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