Restriction of influenza A virus replication by host DCAF7-CRL4B axis

Until now, the key host factors that affect IAV polymerase have not been fully elucidated. In this study, we identified host DCAF7 as a novel restriction factor for IAV replication. Importantly, DCAF7 acts as a substrate recognition receptor to recruit CRL4B E3 ligase to mediate the degradation of PA through the ubiquitin-proteasome pathway. Further exploration demonstrated that a specific cullin-RING E3 ligase inhibitor MLN4924 promotes IAV replication <i>in vivo</i>, and activation of CUL4B by etoposide inhibits IAV replication <i>in vivo</i>. Notably, we found that the viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. These findings elucidate the critical function and mechanism of the DCAF7-CRL4B axis in IAV replication, reveal a novel host anti-IAV mechanism, and provide new anti-influenza drug development strategies.