Interaction and co‐phase separation of SARS ‐ CoV ‐2 nucleocapsid protein and human hnRNPA1 and its implications for viral life cycle

The nucleocapsid (N) protein of SARS‐CoV‐2 is central to viral assembly and replication. It binds the viral RNA to form a helical nucleocapsid and enables genome packaging and its release into host cells. Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), one of the most abundant RNA‐binding proteins in eukaryotes, regulates key aspects of RNA metabolism, including splicing, transcription, localisation, and transport. Here, we report a direct physical interaction between the SARS‐CoV‐2 N protein and hnRNPA1, primarily mediated through their intrinsically disordered regions. Furthermore, we found that these proteins co‐phase separate in vitro and colocalise within stress granules in cells. In vivo studies reveal that hnRNPA1 suppresses viral replication, suggesting that the N protein–hnRNPA1 interaction plays an important role in modulating the viral life cycle.