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J Virol, June 1998, p. 4849-4857, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Major Component of Ikappa Balpha Proteolysis Occurs Independently of the Proteasome Pathway in Respiratory Syncytial Virus-Infected Pulmonary Epithelial Cells

Mohammad Jamaluddin,1 Antonella Casola,2 Roberto P. Garofalo,2 Youqi Han,1 Todd Elliott,2 Pearay L. Ogra,2 and Allan R. Brasier1,*

Department of Medicine and Sealy Center for Molecular Science1 and Department of Pediatrics,2 University of Texas Medical Branch, Galveston, Texas 77555-1060

Received 8 October 1997/Accepted 24 February 1998

Previously we showed that infection of human type II airway epithelial (A549) cells with purified respiratory syncytial virus (pRSV) induced interleukin-8 transcription by a mechanism involving cytokine-inducible cytoplasmic-nuclear translocation of the RelA transcription factor. In unstimulated cells, RelA is tethered in the cytoplasm by association with the Ikappa B inhibitor and can be released only following Ikappa B degradation. In this study, we examined the spectrum of Ikappa B isoform expression and kinetics of proteolysis of the isoforms in A549 cells following pRSV infection. In contrast to the rapid and robust activation of RelA DNA binding that peaked within 15 min of treatment produced by the prototypic activator tumor necrosis factor alpha (TNF-alpha ), pRSV produced a weaker increase in RelA binding that began at 3 h and did not peak until 24 h after infection. A549 cells expressed the Ikappa B inhibitory subunits Ikappa Balpha , Ikappa Bbeta , and p105; however, following either stimulus, only the Ikappa Balpha and Ikappa Bbeta steady-state levels declined in parallel with the increase in RelA DNA-binding activity. The >120-min half-life of Ikappa Balpha in control cells was shortened to 5 min in TNF-alpha -stimulated cells and to 90 min in pRSV-infected cells. Although Ikappa Balpha was resynthesized within 30 min following recombinant human TNFalpha treatment due to a robust 25-fold increase of Ikappa Balpha mRNA expression (the RelA:Ikappa Balpha positive feedback loop), following pRSV infection, there was no reaccumulation of Ikappa Balpha protein, as infected cells produced only a 3-fold increase in Ikappa Balpha mRNA at 24 h, indicating the RelA:Ikappa Balpha positive feedback loop was insufficient to restore control Ikappa Balpha levels. Ikappa Balpha proteolysis induced by TNF-alpha occurred through the 26S proteasome, as both 26S proteasome activity and Ikappa Balpha proteolysis were blocked by specific inhibitors lactacystin, MG-132, and ZLLF-CHO. Although total proteasome activity in 24-h pRSV-infected lysates increased twofold, its activity was >90% inhibited by the proteasome inhibitors; surprisingly, however, Ikappa Balpha proteolysis was not. We conclude that RSV infection produces Ikappa Balpha proteolysis through a mechanism primarily independent of the proteasome pathway.

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

J Virol, June 1998, p. 4849-4857, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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