ZNRD2 Mediated Nucleoprotein Aggregation Impairs Respiratory Syncytial Virus Replication.

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.