# ZNRD2 Mediated Nucleoprotein Aggregation Impairs Respiratory Syncytial Virus Replication

## TL;DR

A host protein called ZNRD2 restricts respiratory syncytial virus replication by forming aggregates with viral nucleoprotein, but the virus can counteract this by preventing aggregate formation.

## Contribution

This study reveals a dual antagonistic mechanism between RSV and ZNRD2, offering new insights into virus-host interactions and antiviral strategies.

## Key findings

- ZNRD2 restricts RSV by promoting insoluble aggregation of the viral nucleoprotein.
- RSV phosphoprotein inhibits ZNRD2-nucleoprotein aggregation to evade host restriction.
- RSV infection causes dynamic changes in ZNRD2 solubility, indicating a complex host-virus interaction.

## Abstract

Nucleoproteins (N) of negative‐sense RNA viruses exhibit an inherent tendency to oligomerize, forming a ribonucleoprotein complex that protects the viral genome. Here, immunoprecipitation coupled with mass spectrometry is used to identify zinc ribbon domain containing 2 (ZNRD2) as a host interactor for the respiratory syncytial virus (RSV) N protein. The results demonstrated that ZNRD2 functions as a restriction factor against RSV by enhancing the oligomerization and insolubility of N. Conversely, RSV N sequesters ZNRD2 into an insoluble aggregate, rendering it incapable of performing physiological functions required for the quality control of chaperonin assembly. Notably, RSV phosphoprotein (P) completely inhibited the formation of the insoluble ZNRD2‐RSV N complex by maintaining N in a monomeric conformation. RSV infection induces a fluctuation in the solubility of ZNRD2, indicating a dynamic interaction between the host protein and the virus. These results reveal a dual antagonistic mechanism, whereby the host uses ZNRD2 to restrain RSV infection by aggregating with N, whereas the virus undermines ZNRD2's physiological functions. This study advances the molecular understanding of virus‐host interactions and may provide insights into the development of novel antiviral strategies against RSV.

During RSV infection, nucleoprotein (N) forms RNA‐bound oligomers. The host protein ZNRD2 binds to these oligomers, promoting their transition into insoluble aggregates. These aggregates simultaneously sequester functional N to restrict viral production and disrupt chaperonin assembly quality control by interfering with ZNRD2's role as an adaptor between E3 ligase and substrates. Additionally, RSV phosphoprotein (P) inhibits the formation of ZNRD2‐N aggregates.