Apoptosis promotes a caspase-induced amino-terminal truncation of I kappa B alpha that functions as a stable inhibitor of NF-kappa B

Caspases are cell death cysteine proteases that are activated upon the indu ction of the apoptotic program and cleave target proteins in a sequence-spe cific manner to promote cell death. Recently, Barkett et al. (Barkett, M., Xue, D., Horvitz, H. R., and Gilmore, T. D. (1997) J. Biol. Chem. 272, 2941 9-29422) have shown that I kappa B alpha, the inhibitory subunit of the tra nscription factor NF-kappa B, can be cleaved by caspase-3 in vitro at a sit e that potentially produces a dominant inhibitory form of I kappa B alpha. The involvement of NF-kappa B in the inhibition of cell death led us to ask whether apoptotic stimuli would induce the caspase-mediated cleavage of I kappa B alpha in vivo. In this study, we show that apoptosis leads to the c aspase-mediated amino-terminal truncation of I kappa B alpha (Delta N-I kap pa B alpha). Our data show that Delta N-I kappa B alpha can bind NF-kappa B , suppress NF-kappa B activation, and sensitize cells to death. Since activ ated NF-kappa B plays a role in the inhibition of cell death, these data su ggest that caspase-mediated cleavage of I kappa B alpha may be a mechanism to suppress NF-kappa B and its associated antiapoptotic activity.