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© The Rockefeller University Press, 0021-9525/1998//1479 $5.00
The Journal of Cell Biology, Volume 141, Number 7, , 1998 1479-1487

Articles

Suppression of Steady-state, but not Stimulus-induced NF-{kappa}B Activity Inhibits Alphavirus-induced Apoptosis



Kuo-I Lin*,||, Joseph A. DiDonato{ddagger}, Alexander Hoffmann§, J. Marie Hardwick*, and Rajiv R. Ratan||

* Department of Molecular Microbiology and Immunology, The Johns Hopkins University School of Public Health, Baltimore, Maryland 21205; {ddagger} Department of Medicine, University of California, San Diego, La Jolla, California 92093; § Department of Biology, Massachusetts Institute of Technology, Boston, Massachusetts 02114; and || Department of Neurology and Program in Neuroscience, Harvard Medical School and Beth Israel-Deaconess Medical Center, Boston, Massachusetts 02115

Recent studies have established cell type– specific, proapoptotic, or antiapoptotic functions for the transcription factor NF-{kappa}B. In each of these studies, inhibitors of NF-{kappa}B activity have been present before the apoptotic stimulus, and so the role of stimulus- induced NF-{kappa}B activation in enhancing or inhibiting survival could not be directly assessed. Sindbis virus, an alphavirus, induces NF-{kappa}B activation and apoptosis in cultured cell lines. To address whether Sindbis virus– induced NF-{kappa}B activation is required for apoptosis, we used a chimeric Sindbis virus that expresses a superrepressor of NF-{kappa}B activity. Complete suppression of virus-induced NF-{kappa}B activity neither prevents nor potentiates Sindbis virus–induced apoptosis. In contrast, inhibition of NF-{kappa}B activity before infection inhibits Sindbis virus–induced apoptosis. Our results demonstrate that suppression of steady-state, but not stimulus-induced NF-{kappa}B activity, regulates expression of gene products required for Sindbis virus–induced death. Furthermore, we show that in the same cell line, NF-{kappa}B can be proapoptotic or antiapoptotic depending on the death stimulus. We propose that the role of NF-{kappa}B in regulating apoptosis is determined by the death stimulus and by the timing of modulating NF-{kappa}B activity relative to the death stimulus.

1. Abbreviations in this paper: EMSA, electrophoretic mobility shift assay; HA, hemagglutinin; M, mutant; NAC, N-acetylcysteine; R, reverse; SV, Sindbis virus; STS, staurosporine; wt, wild-type.

Address all correspondence to Rajiv R. Ratan, M.D., Ph.D., Neurology Laboratories at Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Rm. 857; 77 Avenue Louis Pasteur, Boston, MA 02115.


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