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Microbiology and Molecular Biology Reviews, December 2000, p. 821-846, Vol. 64, No. 4
1092-2172/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Proteases for Cell Suicide: Functions and Regulation of Caspases

Howard Y. Chang1 and Xiaolu Yang2,*

Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Boston, Massachusetts 02115,1 and Department of Molecular and Cellular Engineering and Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, Pennsylvania 191042

Caspases are a large family of evolutionarily conserved proteases found from Caenorhabditis elegans to humans. Although the first caspase was identified as a processing enzyme for interleukin-1beta , genetic and biochemical data have converged to reveal that many caspases are key mediators of apoptosis, the intrinsic cell suicide program essential for development and tissue homeostasis. Each caspase is a cysteine aspartase; it employs a nucleophilic cysteine in its active site to cleave aspartic acid peptide bonds within proteins. Caspases are synthesized as inactive precursors termed procaspases; proteolytic processing of procaspase generates the tetrameric active caspase enzyme, composed of two repeating heterotypic subunits. Based on kinetic data, substrate specificity, and procaspase structure, caspases have been conceptually divided into initiators and effectors. Initiator caspases activate effector caspases in response to specific cell death signals, and effector caspases cleave various cellular proteins to trigger apoptosis. Adapter protein-mediated oligomerization of procaspases is now recognized as a universal mechanism of initiator caspase activation and underlies the control of both cell surface death receptor and mitochondrial cytochrome c-Apaf-1 apoptosis pathways. Caspase substrates have bene identified that induce each of the classic features of apoptosis, including membrane blebbing, cell body shrinkage, and DNA fragmentation. Mice deficient for caspase genes have highlighted tissue- and signal-specific pathways for apoptosis and demonstrated an independent function for caspase-1 and -11 in cytokine processing. Dysregulation of caspases features prominently in many human diseases, including cancer, autoimmunity, and neurodegenerative disorders, and increasing evidence shows that altering caspase activity can confer therapeutic benefits.

* Corresponding author. Mailing address: Department of Molecular and Cellular Engineering, University of Pennsylvania, 421 Curie Blvd., Rm. 610 BRBII/III, Philadelphia, PA 19104-6160. Phone: (215) 573-6739. Fax: (215) 573-8606. E-mail: xyang{at}mail.med.upenn.edu.

Microbiology and Molecular Biology Reviews, December 2000, p. 821-846, Vol. 64, No. 4
1092-2172/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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