The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death.
IFNgamma 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 IFNgamma. Expression of Bik but not mutant BikL61G induces and loss of Bik suppresses IFNgamma-induced cell death in HAECs. IFNgamma 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 IFNgamma- 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 IFNgamma(-/-) or bik(-/-) compared with wild-type mice. These results demonstrate that IFNgamma requires Bik to suppress nuclear localization of phospho-ERK1/2 to channel cell death in AECs.
Mebratu
Yohannes A
YA
Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Dickey
Burton F
BF
Evans
Chris
C
Tesfaigzi
Yohannes
Y
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017304:Annexin A5 / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000502:physiology; D002401:Cathepsin B / Q000235:genetics; D002402:Cathepsin D / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016337:RNA, Catalytic / Q000235:genetics / Q000502:physiology; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C096820:BIK protein, human; C111741:Bik protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016337:RNA, Catalytic; C418481:hairpin ribozyme; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002401:Cathepsin B; D002402:Cathepsin D