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Influenza A virus NS1 protein represses antiviral immune response by hijacking NF-κB to mediate transcription of type III IFN.
Lee, Meng-Chang; Yu, Cheng-Ping; Chen, Xing-Hong; Liu, Ming-Tsan; Yang, Ji-Rong; Chen, An-Yu; Huang, Chih-Heng.
Afiliação
  • Lee MC; School of Public Health, National Defense Medical Center, Taipei, Taiwan.
  • Yu CP; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
  • Chen XH; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
  • Liu MT; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • Yang JR; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Chen AY; Center for Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
  • Huang CH; Center for Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
Front Cell Infect Microbiol ; 12: 998584, 2022.
Article em En | MEDLINE | ID: mdl-36189352
Background: Non-structural protein 1 (NS1), one of the viral proteins of influenza A viruses (IAVs), plays a crucial role in evading host antiviral immune response. It is known that the IAV NS1 protein regulates the antiviral genes response mainly through several different molecular mechanisms in cytoplasm. Current evidence suggests that NS1 represses the transcription of IFNB1 gene by inhibiting the recruitment of Pol II to its exons and promoters in infected cells. However, IAV NS1 whether can utilize a common mechanism to antagonize antiviral response by interacting with cellular DNA and immune-related transcription factors in the nucleus, is not yet clear. Methods: Chromatin immunoprecipitation and sequencing (ChIP-seq) was used to determine genome-wide transcriptional DNA-binding sites for NS1 and NF-κB in viral infection. Next, we used ChIP-reChIP, luciferase reporter assay and secreted embryonic alkaline phosphatase (SEAP) assay to provide information on the dynamic binding of NS1 and NF-κB to chromatin. RNA sequencing (RNA-seq) transcriptomic analyses were used to explore the critical role of NS1 and NF-κB in IAV infection as well as the detailed processes governing host antiviral response. Results: Herein, NS1 was found to co-localize with NF-κB using ChIP-seq. ChIP-reChIP and luciferase reporter assay confirmed the co-localization of NS1 and NF-κB at type III IFN genes, such as IFNL1, IFNL2, and IFNL3. We discovered that NS1 disturbed binding manners of NF-κB to inhibit IFNL1 expression. NS1 hijacked NF-κB from a typical IFNL1 promoter to the exon-intron region of IFNL1 and decreased the enrichment of RNA polymerase II and H3K27ac, a chromatin accessibility marker, in the promoter region of IFNL1 during IAV infection, consequently reducing IFNL1 gene expression. NS1 deletion enhanced the enrichment of RNA polymerase II at the IFNL1 promoter and promoted its expression. Conclusion: Overall, NS1 hijacked NF-κB to prevent its interaction with the IFNL1 promoter and restricted the open chromatin architecture of the promoter, thereby abating antiviral gene expression.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Vírus da Influenza A Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Vírus da Influenza A Idioma: En Ano de publicação: 2022 Tipo de documento: Article