Ubiquilin1 restricts influenza viral replication through trapping vRNP in the late endosomes

Influenza A viruses (IAVs) cause seasonal epidemics and occasional pandemics in humans. Although multiple stages of the viral life cycle have been well characterized, the molecular mechanisms governing viral uncoating remain incompletely understood. Here, we identify the host protein Ubiquilin1 (UBQLN1) as a restriction factor that inhibits IAV uncoating. UBQLN1 interacts with viral ribonucleoproteins (vRNPs), preventing HDAC6-dependent uncoating and sequestering vRNPs in late endosomes. In addition, UBQLN1 disrupts the interaction between vRNPs and importins, thereby impairing nuclear import of vRNPs. Functionally, UBQLN1 restricts replication of multiple influenza virus strains both in vitro and in vivo. UBQLN1 knockout increases cellular susceptibility to infection and promotes viral replication, and loss of Ubqln1 in mice leads to higher viral loads and exacerbated disease severity. These findings identify UBQLN1 as a host factor that blocks influenza infection by targeting viral uncoating and suggest a potential antiviral strategy.