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Published online
doi:10.1083/jcb.200801186
The Journal of Cell Biology, Vol. 183, No. 3, 429-439
The Rockefeller University Press, 0021-9525 $30.00
© Mebratu et al.
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Article

The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFN{gamma}-induced cell death



Yohannes A. Mebratu1, Burton F. Dickey2, Chris Evans2, and Yohannes Tesfaigzi1

1 Lovelace Respiratory Research Institute, Albuquerque, NM 87108
2 Department of Pulmonary Medicine, M.D. Anderson Cancer Center, Houston, TX 77030

Correspondence to Y. Tesfaigzi: ytesfaig{at}lrri.org

IFN{gamma} induces cell death in epithelial cells, but the mediator for this death pathway has not been identified. In this study, we find that expression of Bik/Blk/Nbk is increased in human airway epithelial cells (AECs [HAECs]) in response to IFN{gamma}. Expression of Bik but not mutant BikL61G induces and loss of Bik suppresses IFN{gamma}-induced cell death in HAECs. IFN{gamma} treatment and Bik expression increase cathepsin B and D messenger RNA levels and reduce levels of phospho–extracellular regulated kinase 1/2 (ERK1/2) in the nuclei of bik+/+ compared with bik–/– murine AECs. Bik but not BikL61G interacts with and suppresses nuclear translocation of phospho-ERK1/2, and suppression of ERK1/2 activation inhibits IFN{gamma}- and Bik-induced cell death. Furthermore, after prolonged exposure to allergen, hyperplastic epithelial cells persist longer, and nuclear phospho-ERK is more prevalent in airways of IFN{gamma}–/– or bik–/– compared with wild-type mice. These results demonstrate that IFN{gamma} requires Bik to suppress nuclear localization of phospho-ERK1/2 to channel cell death in AECs.

Abbreviations used in this paper: AB, Alcian blue; AEC, airway epithelial cell; BH, Bcl-2 homology; CT, control; DAP, death-associated protein; ERK, extracellular regulated kinase; HAEC, human AEC; MAEC, mouse AEC; shRNA, short hairpin RNA.

© 2008 Mebratu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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