Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3under pathological conditions

Caspase-11,a member of the murine caspase family, has been shown to be an u pstream activator of caspase-1 in regulating cytokine maturation. We demons trate here that in addition to its defect in cytokine maturation, caspase-1 1-deficient mice have a reduced number of apoptotic cells and a defect in c aspase-3 activation after middle cerebral artery occlusion (MCAO), a mouse model of stroke. Recombinant procaspase-11 can autoprocess itself in vitro. Purified active recombinant caspase-11 cleaves and activates procaspase-3 very efficiently. Using a positional scanning combinatorial library method, we found that the optimal cleavage site of caspase-11 was (I/L/V/P)EHD, si milar to that of upstream caspases such as caspase-8 and -9. Our results su ggest that caspase-11 is a critical initiator caspase responsible for the a ctivation of caspase-3, as well as caspase-1. under certain pathological co nditions.