Proteases for cell suicide: Functions and regulation of caspases

Caspases are a large family of evolutionarily conserved proteases found fr om Caenorhabditis elegans to humans. Although the first caspase was identif ied as a processing enzyme for interleukin-1 beta, genetic and biochemical data have converged to reveal that many caspases are key mediators of apopt osis, the intrinsic cell suicide program essential for development and tiss ue homeostasis. Each caspase is a cysteine aspartase; it employs a nucleoph ilic cysteine in its active site to cleave aspartic acid peptide bonds with in proteins. Caspases are synthesized as inactive precursors ter-med procas pases; proteolytic processing of procaspase generates the tetrameric active caspase enzyme, composed of two repeating heterotypic subunits. Based on k inetic 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. A dapter protein-mediated oligomerization of procaspases is now recognized as a universal mechanism of initiator caspase activation and underlies the co ntrol of both cell surface death receptor and mitochondrial cytochrome c-Ap af-1 apoptosis pathways. Caspase substrates have bene identified that induc e each of the classic features of apoptosis, including membrane blebbing, c ell body shrinkage, and DNA fragmentation. Mice deficient for caspase genes have highlighted tissue- and signal-specific pathways for apoptosis and de monstrated an independent function for caspase-1 and -11 in cytokine proces sing. Dysregulation of caspases features prominently in many human diseases , including cancel; autoimmunity, and neurodegenerative disorders and incre asing evidence shows that altering caspase activity can confer therapeutic benefits.