Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions.
Caspase-11, a member of the murine caspase family, has been shown to be an upstream activator of caspase-1 in regulating cytokine maturation. We demonstrate here that in addition to its defect in cytokine maturation, caspase-11-deficient mice have a reduced number of apoptotic cells and a defect in caspase-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, similar to that of upstream caspases such as caspase-8 and -9. Our results suggest that caspase-11 is a critical initiator caspase responsible for the activation of caspase-3, as well as caspase-1 under certain pathological conditions.
Kang
S J
SJ
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wang
S
S
Hara
H
H
Peterson
E P
EP
Namura
S
S
Amin-Hanjani
S
S
Huang
Z
Z
Srinivasan
A
A
Tomaselli
K J
KJ
Thornberry
N A
NA
Moskowitz
M A
MA
Yuan
J
J
D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D011498:Protein Precursors / Q000378:metabolism; D011994:Recombinant Proteins; D020521:Stroke / Q000201:enzymology; D013379:Substrate Specificity
D061945:Caspase Inhibitors; D016207:Cytokines; D011498:Protein Precursors; D011994:Recombinant Proteins; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1