Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation

Ecco Staller, Loïc Carrique, Olivia C. Swann, Haitian Fan, Jeremy R. Keown, Carol M. Sheppard, Wendy S. Barclay, Jonathan M. Grimes () and Ervin Fodor ()
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Ecco Staller: University of Oxford
Loïc Carrique: University of Oxford
Olivia C. Swann: Imperial College London
Haitian Fan: University of Oxford
Jeremy R. Keown: University of Oxford
Carol M. Sheppard: Imperial College London
Wendy S. Barclay: Imperial College London
Jonathan M. Grimes: University of Oxford
Ervin Fodor: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Avian influenza A viruses (IAVs) pose a public health threat, as they are capable of triggering pandemics by crossing species barriers. Replication of avian IAVs in mammalian cells is hindered by species-specific variation in acidic nuclear phosphoprotein 32 (ANP32) proteins, which are essential for viral RNA genome replication. Adaptive mutations enable the IAV RNA polymerase (FluPolA) to surmount this barrier. Here, we present cryo-electron microscopy structures of monomeric and dimeric avian H5N1 FluPolA with human ANP32B. ANP32B interacts with the PA subunit of FluPolA in the monomeric form, at the site used for its docking onto the C-terminal domain of host RNA polymerase II during viral transcription. ANP32B acts as a chaperone, guiding FluPolA towards a ribonucleoprotein-associated FluPolA to form an asymmetric dimer—the replication platform for the viral genome. These findings offer insights into the molecular mechanisms governing IAV genome replication, while enhancing our understanding of the molecular processes underpinning mammalian adaptations in avian-origin FluPolA.

Date: 2024
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DOI: 10.1038/s41467-024-48470-3

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