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© The Rockefeller University Press, 0021-9525/2000//613 $5.00
The Journal of Cell Biology, Volume 149, Number 3, , 2000 613-622

Original Article

Dual Role of Caspase-11 in Mediating Activation of Caspase-1 and Caspase-3 under Pathological Conditions



Shin-Jung Kanga, Suyue Wanga, Hideaki Harab, Erin P. Petersonc, Shobu Namurab, Sepideh Amin-Hanjanib, Zhihong Huangb, Anu Srinivasand, Kevin J. Tomasellid, Nancy A. Thornberryc, Michael A. Moskowitzb, and Junying Yuana

a Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
b Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129
c Department of Enzymology, Merck Research Laboratories, Rahway, New Jersey 07065
d Idun Pharmaceuticals, Inc., La Jolla, California 92037
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115.617 432-4177617 432-4170

jyuan{at}hms.harvard.edu

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.

Key Words: caspase-11 • initiator caspase • stroke • middle cerebral artery occlusion • apoptosis

© 2000 The Rockefeller University Press

Shin-Jung Kang and Suyue Wang contributed to this work equally.

Abbreviations used in this paper: GFAP, glial fibrillary acidic protein; IL-1β, interleukin-1β; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; PS-SCL, positional scanning-synthetic combinatorial library; TUNEL, TdT-mediated dUTP-digoxigenin nick-end labeling.


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