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Journal of Virology, December 2005, p. 15302-15313, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15302-15313.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Respiratory Syncytial Virus-Inducible BCL-3 Expression Antagonizes the STAT/IRF and NF-{kappa}B Signaling Pathways by Inducing Histone Deacetylase 1 Recruitment to the Interleukin-8 Promoter

Mohammad Jamaluddin,1 Sanjeev Choudhary,1,6 Shaofei Wang,1 Antonella Casola,2 Ruksana Huda,5 Roberto P. Garofalo,2,3 Sutapa Ray,1 and Allan R. Brasier1,4*

Departments of Medicine,1 Pediatrics,2 Microbiology and Immunology,3 Anesthesiology,5 Human Biological Chemistry and Genetics,6 Sealy Center for Molecular Sciences, The University of Texas Medical Branch, Galveston, Texas 77555-10604

Received 8 July 2005/ Accepted 8 September 2005

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-{kappa}B/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-{kappa}B and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-{kappa}B1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-{kappa}B1 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-{kappa}B and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.

* Corresponding author. Mailing address: Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Phone: (409) 772-2824. Fax: (409) 772-8709. E-mail: arbrasie{at}utmb.edu.

Journal of Virology, December 2005, p. 15302-15313, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15302-15313.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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