Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway.

Nbk/Bik (natural born killer/Bcl-2-interacting killer) is a tissue-specific BH3-only protein whose molecular function is still largely unknown. To investigate the mechanism of Nbk action, we established a single- vector adenoviral system based on the Tet-off conditional expression of Nbk. Upon Nbk expression, only Bax-positive, but not Bax-deficient cells were found ...
to undergo apoptosis. Interestingly, Nbk failed to induce apoptosis in the absence of Bax, even despite expression of the related molecule Bak. Re-expression of Bax restored the sensitivity to Nbk. Similarly, Bax wild-type HCT116 cells were highly susceptible, whereas HCT116 Bax knock-out cells remained resistant to Nbk-induced apoptosis. In Bax-positive cells, Nbk induced a conformational switch in the Bax N-terminus coinciding with cytochrome c release, mitochondrial permeability transition and caspase-9 processing. Immunoprecipitation studies revealed that Nbk interacts with Bcl-x(L) and Bcl-2 but not with Bax. Since, in addition, Nbk did not localize to the mitochondria, our data suggest a model in which Nbk acts as an indirect killer to trigger Bax-dependent apoptosis, whereas Bak is not sufficient to confer sensitivity to Nbk.
Mesh Terms:
Adenoviridae, Amino Acid Sequence, Apoptosis, Apoptosis Regulatory Proteins, Caspases, Cell Line, Cytochrome c Group, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Viral, Humans, Intracellular Membranes, Membrane Proteins, Mitochondria, Protein Conformation, Protein Isoforms, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Recombinant Proteins, Tumor Cells, Cultured, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
EMBO J.
Date: Jul. 15, 2003
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