Antiapoptotic activity of the free caspase recruitment domain of procaspase-9: a novel endogenous rescue pathway in cell death

Mitochondrial injury initiates proteolytic processing of procaspase-9 into the large and small subunits, leading to apoptotic cell death. Here we show that the free caspase recruitment domain (CARD) released by procaspase-9 processing activates nuclear factor kappaB expression. A procaspase-9 construct with a point mutation that abrogates the release of the CARD abolished nuclear factor kappaB activation. Most importantly, the free CARD is shown to enhance the expression of the gene encoding the antiapoptotic Bcl-x protein and to strongly inhibit apoptosis. This is the first demonstration that different domains of the same caspase protein have proapoptotic and antiapoptotic effects and suggests that the relative effects of these domains are important in regulating the balance between death and survival.