Respiratory syncytial virus-inducible BCL-3 expression antagonizes the STAT/IRF and NF-kappaB signaling pathways by inducing histone deacetylase 1 recruitment to the interleukin-8 promoter.

Abstract

Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.

• Authors: Mohammad Jamaluddin, Sanjeev Choudhary, Shaofei Wang, Antonella Casola, Ruksana Huda, Roberto P Garofalo, Sutapa Ray, Allan R Brasier
• Journal: Journal of virology (J Virol) Vol. 79 Issue 24 Pg. 15302-13 (Dec 2005) ISSN: 0022-538X [Print] United States
• PMID: 16306601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Interleukin-8
• N4BP2 protein, human
• NF-kappa B
• STAT Transcription Factors
• Tumor Necrosis Factor-alpha
• HDAC1 protein, human
• Histone Deacetylase 1
• Histone Deacetylases
• DNA Repair Enzymes

Topics

• Carrier Proteins (metabolism)
• Cells, Cultured
• DNA Repair Enzymes
• Gene Expression Regulation, Viral (drug effects, physiology)
• Histone Deacetylase 1
• Histone Deacetylases (genetics, metabolism)
• Humans
• Interleukin-8 (genetics)
• NF-kappa B (physiology)
• Promoter Regions, Genetic
• Respiratory Syncytial Viruses (physiology)
• STAT Transcription Factors (physiology)
• Signal Transduction (drug effects, physiology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)