The BH3-only protein BikJBlkJNbk inhibits nuclear translocation of activated ERK1J2 to mediate IFNγ-induced cell death

Abstract

IFNγ 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 BikJBlkJNbk is increased in human airway epithelial cells (AECs [HAECs]) in response to IFNγ. Expression of Bik but not mutant BikL61 G induces and loss of Bik suppresses IFNγ-induced cell death in HAECs. IFNγ treatment and Bik expression increase cathepsin B and D messenger RNA levels and reduce levels of phospho-extracellular regulated kinase 1 J2 (ERK1 J2) in the nuclei of bik +J+ compared with bik -J- murine AECs. Bik but not BikL61 G interacts with and suppresses nuclear translocation of phospho-ERK1J2, and suppression of ERK1 J2 activation inhibits IFNγ- and Bikinduced cell death. Furthermore, after prolonged exposure to allergen, hyperplastic epithelial cells persist longer, and nuclear phospho-ERK is more prevalent in airways of lFN -J- or bik -J- compared with wild-type mice. These results demonstrate that IFNγ requires Bik to suppress nuclear localization of phospho-ERK1 J2 to channel cell death in AECs. © 2008 Mebratu et al.