Host ANP32A mediates the assembly of the influenza virus replicase

Host ANP32A mediates the assembly of the influenza virus replicase

Avian influenza (colloquially known as bird flu), is a viral infection caused by viruses that primarily affect birds, such as waterfowl and poultry. However, these viruses can also infect humans, leading to potentially lethal infections. Upon avian to mammalian transmission adaptive mutations occur in the viral genome, including in the genes encoding the RNA polymerase. Understanding how avian influenza viruses adapt to mammalian host species can provide the knowledge necessary for potential therapeutics against the disease, or the genetic engineering of domesticated animals resistant to infection.

Recently, Dr. Haitian Fan and graduate student Alex Walker in Professor Ervin Fodor’s group in the Dunn School, collaborating with Professor Jonathan Grimes’ group in the Division of Structural Biology at Oxford, have used cryo-electron microscopy to determine the structure of the RNA polymerase in influenza C viruses (FluPolC). They report the structure of FluPolC alone and in complex with both chicken and human acidic nuclear phosphoprotein 32A (ANP32A), an essential host protein for polymerase activity.

Importantly, these structures revealed possible molecular mechanisms by which influenza viruses replicate their RNA genome. An asymmetric dimer of FluPolC complexes with ANP32A, and the 627-domain of the PB2 subunit, where adaptive mutations accumulate, interacts with an acidic region of ANP32A. The acidic nature of this region could explain how a certain mutation eliminating an acidic residue in the equivalent PB2 subunit in FluPolA enables avian influenza A viruses to infect humans.

Additionally, this study proposes a potential mechanism by which one of the two RNA polymerases in the asymmetric dimer functions as a replicase to replicate the viral genome, while the other RNA polymerase functions as an “encapsidating” polymerase, which assembles nascent RNA product into ribonucleoprotein complexes, and eventually, viruses.

Derek Xu

Carrique L, Fan H, Walker AP, Keown JR, Sharps J , Staller E, Barclay WS, Fodor E and Grimes JM (2020).

Nature (587) 638–643  https://doi.org/10.1038/s41586-020-2927-z