Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-kB

Abstract

Caspases are cell death cysteine proteases that are activated upon the induction of the apoptotic program and cleave target proteins in a sequence- specific 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, 29419- 29422) have shown that IκBα, the inhibitory subunit of the transcription factor NF-κB, can be cleaved by caspase-3 in vitro at a site that potentially produces a dominant inhibitory form of IκBα. The involvement of NF-κB in the inhibition of cell death led us to ask whether apoptotic stimuli would induce the caspase-mediated cleavage of IκBα in vivo. In this study, we show that apoptosis leads to the caspase-mediated amino-terminal truncation of IκBα (δN-IκBα). Our data show that δN-IκBα can bind NF- κB, suppress NF-κB activation, and sensitize cells to death. Since activated NF-κB plays a role in the inhibition of cell death, these data suggest that caspase-mediated cleavage of IκBα may be a mechanism to suppress NF-κB and its associated antiapoptotic activity.