# Cellular hnRNP AB inhibits avian influenza virus RNA synthesis via blocking UAP56-mediated nuclear export of PB2 mRNA

## TL;DR

This study shows how a host protein, hnRNP AB, inhibits avian influenza virus replication by blocking the nuclear export of a key viral mRNA.

## Contribution

The study identifies the glycine-rich domain of hnRNP AB as the functional region that inhibits AIV replication by interfering with UAP56-mediated PB2 mRNA export.

## Key findings

- Avian hnRNP AB inhibits replication of multiple avian influenza virus subtypes.
- The GRD of hnRNP AB interacts with PB2, disrupting RdRp assembly and vRNA synthesis.
- hnRNP AB reduces UAP56 binding to PB2 mRNA, decreasing PB2 expression and viral replication.

## Abstract

Avian influenza viral ribonucleoproteins (vRNPs) complete genome transcription and replication by interacting with host proteins, and RNA-dependent RNA polymerase (RdRp) is its major component. PB2 is a component of RdRp and plays an important role in viral RNA synthesis. Our previous mass spectrometry analysis identified PB2 interacted with avian cellular heterogeneous nuclear ribonucleoprotein AB (hnRNP AB). However, the specific mechanism of this interaction regulating viral replication needs to be further clarified. In this study, we found that avian hnRNP AB inhibited the replication of multiple subtypes of avian influenza viruses (AIVs) from different reservoirs, and the glycine-rich domain (GRD) of hnRNP AB was the function domain that inhibited AIV replication. Moreover, we demonstrated that the GRD of avian hnRNP AB interacted with the C-terminus of PB2, reducing the binding of PB1 to PB2 and interfering with RdRp assembly. Based on the previous discovery that hnRNP AB affected the nucleoplasmic distribution of PB2 mRNA, we have further explored the mechanism here. Mechanically, hnRNP AB intervened in the nuclear export of PB2 mRNA by reducing the binding ability of UAP56, and decreased PB2 expression to interfere with RdRp formation and reduce vRNA synthesis, which in turn inhibited viral replication. Collectively, this study demonstrated that the avian host protein hnRNP AB inhibited AIV replication by blocking assembly of RdRp and vRNA synthesis, in which was associated with UAP56-mediated nuclear export of PB2 mRNA, providing a potential target for antiviral intervention.