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Journal of Virology, July 2005, p. 8948-8959, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8948-8959.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Respiratory Syncytial Virus Influences NF-{kappa}B-Dependent Gene Expression through a Novel Pathway Involving MAP3K14/NIK Expression and Nuclear Complex Formation with NF-{kappa}B2

Sanjeev Choudhary,1,2 Steve Boldogh,3 Roberto Garofalo,3,4 Mohammad Jamaluddin,1 and Allan R. Brasier1,5*

Departments of Medicine,1 Human Biological Chemistry and Genetics,2 Microbiology and Immunology,3 Pediatrics,4 Sealy Center for Molecular Science, The University of Texas Medical Branch, Galveston, Texas 77555-10605

Received 3 January 2005/ Accepted 30 March 2005

A member of the Paramyxoviridae family of RNA viruses, respiratory syncytial virus (RSV), is a leading cause of epidemic respiratory tract infection in children. In children, RSV primarily replicates in the airway mucosa, a process that alters epithelial cell chemokine expression, thereby inducing airway inflammation. We investigated the role of the mitogen-activated protein kinase kinase kinase 14/NF-{kappa}B-inducing kinase (NIK) in the activation of NF-{kappa}B-dependent genes in alveolus-like A549 cells. RSV infection induces a time dependent increase of NIK mRNA and protein expression that peaks 12 to 24 h after viral exposure. Immunoprecipitation kinase assays indicate that NIK kinase activity is activated even more rapidly (within 6 h of RSV adsorption) associated with an endogenous ~50-kDa NF-{kappa}B2 substrate. Because NIK associates with IKK{alpha} to mediate processing of the 100-kDa NF-{kappa}B2 precursor into its 52-kDa DNA binding isoform ("p52"), the effects of RSV on NIK complex formation with IKK{alpha} and NF-{kappa}B2 were determined by coimmunoprecipitation assay. We find that NIK, IKK{alpha}, and both 100 kDa- and 52-kDa NF-{kappa}B2 isoforms strongly complex 15 h after exposure to RSV at times subsequent to NIK kinase activation. Western immunoblot and microaffinity DNA pull-down assays showed a parallel increase in nuclear translocation and DNA binding of the NF-{kappa}B2-Rel B complex. Interestingly, we make the novel observations that NIK also transiently translocates into the nucleus complexed with 52-kDa NF-{kappa}B2. Small interfering RNA-mediated NIK "knock-down" blocked RSV-inducible 52-kDa NF-{kappa}B2 processing and interfered with the early activation of a subset of NF-{kappa}B-dependent genes, indicating the importance of this activation pathway in the genomic NF-{kappa}B response to RSV. Together, these data indicate that RSV infection rapidly activates the noncanonical NF-{kappa}B activation pathway prior to the more potent canonical pathway activation. This appears to be through a novel mechanism involving induction of NIK kinase activity, expression, and nuclear translocation of a ternary complex with IKK{alpha} and processed NF-{kappa}B2.

* 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, July 2005, p. 8948-8959, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8948-8959.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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