The Domains of Apoptosis: A Genomics Perspective

Apoptosis plays important roles in many facets of normal physiology in animal species, including programmed cell death associated with fetal development or metamorphosis, tissue homeostasis, immune cell education, and some aspects of aging. Defects in the regulation of apoptosis contribute to multiple diseases associated with either inappropriate cell loss or pathological cell accumulation. Host-pathogen interactions have additionally provided evolutionary pressure for apoptosis as a defense mechanism against viruses and microbes, sometimes linking apoptosis mechanisms with inflammatory responses. To a large extent, the apoptosis machinery can be viewed as a network, with different nodes connected by physical interactions of evolutionarily conserved domains. These domains can serve as signatures for identification of proteins involved in the network. In particular, the caspase recruitment domains (CARDs); death effector domains (DEDs); death domains (DDs); BIR (baculovirus IAP repeat) domains of inhibitor of apoptosis proteins (IAPs); Bcl-2 family proteins; caspase protease domains; and endonuclease-associated CIDE (cell death–inducing DFF45-like effector) domains are found in common in proteins involved in apoptosis. In the genomes of mammals, genes encoding proteins that carry one or more of these signature domains are often present in multiple copies, making up diverse gene families that permit tissue-specific and highly regulated control of cell life and death decisions through combinations of stimulus-specific gene expression and complex protein interaction networks. In this Review, we organize the repertoire of apoptosis proteins of humans into domain families, drawing comparisons with homologs in other vertebrate and invertebrate animal species, and discuss some of the functional implications of these findings. Programmed cell death, also known as apoptosis, plays important roles in many aspects of normal physiology in animal species, including programmed death associated with fetal development or metamorphosis, tissue homeostasis, elimination of inappropriate cells in the immune system, and some aspects of aging. Defects in the regulation of apoptosis contribute to multiple diseases; for example, lack of apoptosis contributes to cancer, and excessive apoptosis is associated with neurodegenerative and autoimmune diseases. Apoptosis also functions as a defense mechanism against viruses and microbes. In the regulatory machinery that contols apoptosis, interactions between key proteins are determined by small protein segments or domains that allow cells to react appropriately to signals from within or outside the cell. In this Review, we examine the range of human proteins that contain these domains and discuss how the resultant protein interactions help control cell death. These same domains provide possible targets for the development of drugs that could beneficially modulate apoptosis.