Lei Yu, Yong Jiang, Hongyu Rang, Xueyun Wang, Yumeng Cai, Haojie Yan, Shuwen Wu, Ke Lan
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引用次数: 0
Abstract
The balance between cellular defense and viral escape determines the fate of influenza A virus (IAV) infection. Viral polymerase activity is critical for the replication and propagation of IAV. The antiviral strategies of host cells against IAV infection have not been fully elucidated. Here, we identified DCAF7 as an antiviral factor for IAV, which inhibits the replication of H1N1 and H3N2. Mechanistically, DCAF7 weakens the viral heterotrimer polymerase activity and restricts IAV replication and transcription. DCAF7 as a substrate recognition receptor forms a complete CRL4BDCAF7 E3 ligase with the CRL4B E3 complex to promote K48-linked polyubiquitination of the viral polymerase subunit PA at the K609 site and its degradation. We also showed that a specific cullin-RING E3 ligase (CRL) inhibitor MLN4924 upregulates the protein level of PA and promotes the replication of IAV in vivo. Moreover, activation of CUL4B by etoposide promotes the degradation of PA and inhibits IAV replication in vivo. Importantly, we found that viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. Taken together, these findings reveal a new mechanism of host resistance to IAV infection and suggest that regulation of the DCAF7-CRL4B axis is a potential target for antivirals.
Importance: 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 in vivo, and activation of CUL4B by etoposide inhibits IAV replication in vivo. 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.
期刊介绍:
Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.