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J Virol
. 2026 Jun 12:e0067426.
doi: 10.1128/jvi.00674-26. Online ahead of print.
Gga-miR-92-targeted TNFRSF1B inhibits the replication of influenza A virus by degrading TRAF3
Zhiyuan Liu 1 , Menglu Fan 1 , Yiran Zeng 1 , Yiqing Zheng 1 , Lulu Deng 1 , Lingcai Zhao 1 , Jun Xia 2 , Jihui Ping 1
Affiliations
Influenza viruses represent a significant threat to global public health. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, play pivotal roles in regulating gene expression and have emerged as critical modulators of host-virus interactions. To investigate the functions of miRNAs during influenza virus infection, a miRNA library was constructed and sequenced using DF1 cells infected with the H9N2 influenza virus. From the differentially expressed miRNAs, we identified miR-92 as a key antiviral host factor. Mechanistically, miR-92 inhibits viral replication by targeting TNFRSF1B, which, in turn, enhances type I interferon signaling responses. Promoter region analysis demonstrated that the transcription factor OCT1 binds to the miR-92 promoter and positively regulates its transcriptional activity. Additionally, our study revealed that TNFRSF1B interacts with TNF receptor-associated factor 3 (TRAF3) and mediates TRAF3 degradation via the autophagolysosomal pathway. Specifically, TNFRSF1B facilitates the removal of K63-linked polyubiquitin chains from TRAF3. Collectively, these findings indicate that TNFRSF1B negatively regulates IFN-I responses through autophagolysosomal-mediated TRAF3 degradation, while miR-92 counteracts this inhibitory effect to exert antiviral activity. In summary, our research delineates a novel regulatory axis that modulates the interferon pathway and H9N2 influenza virus replication, providing new insights into host antiviral defense mechanisms and potential therapeutic targets.IMPORTANCEThe miR-17-92 cluster is a well-established key regulator of viral infection. However, the specific role of miR-92, an essential member of this cluster, in modulating avian influenza virus infection remains poorly defined. Here, we demonstrate that avian miR-92 exerts robust antiviral activity by directly inhibiting AIV replication. Critically, we report for the first time that the transcription factor OCT1 binds to the promoter region of miR-92 and transcriptionally regulates its expression. Mechanistically, miR-92 targets TNFRSF1B to enhance type I interferon production. Strikingly, TNFRSF1B mediates the degradation of TRAF3, thereby dampening IFN-I signaling. Together, our findings establish miR-92 as a pivotal antiviral effector during AIV infection. Beyond advancing our understanding of small RNA-mediated control of influenza virus replication, this work identifies miR-92 and its regulatory network as promising targets for the development of miRNA-based antiviral therapeutics.
Keywords: OCT1; RNA-seq; TNFRSF1B; TRAF3; miR-92.
. 2026 Jun 12:e0067426.
doi: 10.1128/jvi.00674-26. Online ahead of print.
Gga-miR-92-targeted TNFRSF1B inhibits the replication of influenza A virus by degrading TRAF3
Zhiyuan Liu 1 , Menglu Fan 1 , Yiran Zeng 1 , Yiqing Zheng 1 , Lulu Deng 1 , Lingcai Zhao 1 , Jun Xia 2 , Jihui Ping 1
Affiliations
- PMID: 42283462
- DOI: 10.1128/jvi.00674-26
Influenza viruses represent a significant threat to global public health. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, play pivotal roles in regulating gene expression and have emerged as critical modulators of host-virus interactions. To investigate the functions of miRNAs during influenza virus infection, a miRNA library was constructed and sequenced using DF1 cells infected with the H9N2 influenza virus. From the differentially expressed miRNAs, we identified miR-92 as a key antiviral host factor. Mechanistically, miR-92 inhibits viral replication by targeting TNFRSF1B, which, in turn, enhances type I interferon signaling responses. Promoter region analysis demonstrated that the transcription factor OCT1 binds to the miR-92 promoter and positively regulates its transcriptional activity. Additionally, our study revealed that TNFRSF1B interacts with TNF receptor-associated factor 3 (TRAF3) and mediates TRAF3 degradation via the autophagolysosomal pathway. Specifically, TNFRSF1B facilitates the removal of K63-linked polyubiquitin chains from TRAF3. Collectively, these findings indicate that TNFRSF1B negatively regulates IFN-I responses through autophagolysosomal-mediated TRAF3 degradation, while miR-92 counteracts this inhibitory effect to exert antiviral activity. In summary, our research delineates a novel regulatory axis that modulates the interferon pathway and H9N2 influenza virus replication, providing new insights into host antiviral defense mechanisms and potential therapeutic targets.IMPORTANCEThe miR-17-92 cluster is a well-established key regulator of viral infection. However, the specific role of miR-92, an essential member of this cluster, in modulating avian influenza virus infection remains poorly defined. Here, we demonstrate that avian miR-92 exerts robust antiviral activity by directly inhibiting AIV replication. Critically, we report for the first time that the transcription factor OCT1 binds to the promoter region of miR-92 and transcriptionally regulates its expression. Mechanistically, miR-92 targets TNFRSF1B to enhance type I interferon production. Strikingly, TNFRSF1B mediates the degradation of TRAF3, thereby dampening IFN-I signaling. Together, our findings establish miR-92 as a pivotal antiviral effector during AIV infection. Beyond advancing our understanding of small RNA-mediated control of influenza virus replication, this work identifies miR-92 and its regulatory network as promising targets for the development of miRNA-based antiviral therapeutics.
Keywords: OCT1; RNA-seq; TNFRSF1B; TRAF3; miR-92.