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

Mohammad Jamaluddin, Sanjeev Choudhary, Shaofei Wang, Antonella Casola, Ruksana Huda, Roberto P. Garofalo, Sutapa Ray, Allan R. Brasier

Research output: Contribution to journalArticle

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

Original languageEnglish (US)
Pages (from-to)15302-15313
Number of pages12
JournalJournal of virology
Volume79
Issue number24
DOIs
StatePublished - Dec 1 2005

Fingerprint

Histone Deacetylase 1
histone deacetylase
Respiratory Syncytial Viruses
interleukin-8
B-Cell Lymphoma
lymphoma
Interleukin-8
B-lymphocytes
promoter regions
viruses
transcription (genetics)
Proteins
proteins
chemokines
Chemokines
Viruses
Immunoprecipitation
trichostatin A
Respirovirus
CXC Chemokines

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Respiratory syncytial virus-inducible BCL-3 expression antagonizes the STAT/IRF and NF-κB signaling pathways by inducing histone deacetylase 1 recruitment to the interleukin-8 promoter. / Jamaluddin, Mohammad; Choudhary, Sanjeev; Wang, Shaofei; Casola, Antonella; Huda, Ruksana; Garofalo, Roberto P.; Ray, Sutapa; Brasier, Allan R.

In: Journal of virology, Vol. 79, No. 24, 01.12.2005, p. 15302-15313.

Research output: Contribution to journalArticle

Jamaluddin, Mohammad ; Choudhary, Sanjeev ; Wang, Shaofei ; Casola, Antonella ; Huda, Ruksana ; Garofalo, Roberto P. ; Ray, Sutapa ; Brasier, Allan R. / Respiratory syncytial virus-inducible BCL-3 expression antagonizes the STAT/IRF and NF-κB signaling pathways by inducing histone deacetylase 1 recruitment to the interleukin-8 promoter. In: Journal of virology. 2005 ; Vol. 79, No. 24. pp. 15302-15313.
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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-κB/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-κB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-κB isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-κB 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 {"}knock-down{"} 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-κB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.",
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AU - Choudhary, Sanjeev

AU - Wang, Shaofei

AU - Casola, Antonella

AU - Huda, Ruksana

AU - Garofalo, Roberto P.

AU - Ray, Sutapa

AU - Brasier, Allan R.

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