title: The apoptotic initiator caspase-8: its functional ubiquity and genetic diversity during animal evolution.
abstract: The caspases, a family of cysteine proteases, play multiple roles in apoptosis, inflammation, and cellular differentiation. Caspase-8 (Casp8), which was first identified in humans, functions as an initiator caspase in the apoptotic signaling mediated by cell-surface death receptors. To understand the evolution of function in the Casp8 protein family, casp8 orthologs were identified from a comprehensive range of vertebrates and invertebrates, including sponges and cnidarians, and characterized at both the gene and protein levels. Some introns have been conserved from cnidarians to mammals, but both losses and gains have also occurred; a new intron arose during teleost evolution, whereas in the ascidian Ciona intestinalis, the casp8 gene is intronless and is organized in an operon with a neighboring gene. Casp8 activities are near ubiquitous throughout the animal kingdom. Exogenous expression of a representative range of nonmammalian Casp8 proteins in cultured mammalian cells induced cell death, implying that these proteins possess proapoptotic activity. The cnidarian Casp8 proteins differ considerably from their bilaterian counterparts in terms of amino acid residues in the catalytic pocket, but display the same substrate specificity as human CASP8, highlighting the complexity of spatial structural interactions involved in enzymatic activity. Finally, it was confirmed that the interaction with an adaptor molecule, Fas-associated death domain protein, is also evolutionarily ancient. Thus, despite structural diversity and cooption to a variety of new functions, the ancient origins and near ubiquitous distribution of this activity across the animal kingdom emphasize the importance and utility of Casp8 as a central component of the metazoan molecular toolkit.
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan sakamaki.kazuhiro.7u@kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sakamaki
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Multi-Scale Research Center for Medical Science, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Zoology, Graduate School of Science, Kyoto University, Kyoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Satou
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Funayama
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Nozaki
authors.affiliation: Bio Med Molecular, Cellular Biology Biochemistry Department, Brown University, Providence, RI.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yajima
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nishimura
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Mayura
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Michi
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Marine Environmental Biology, University of Southern California, Los Angeles, CA.
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Gracey
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tomii
authors.affiliation: Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Gotoh
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Akasaka
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.affiliation: Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000845:Annelida / Q000235:genetics; D037421:Anthozoa / Q000235:genetics; D017209:Apoptosis; D001483:Base Sequence; D053181:Caspase 8 / Q000737:chemistry / Q000235:genetics*; D002938:Ciona intestinalis / Q000235:genetics; D019143:Evolution, Molecular; D029941:Fish Proteins / Q000235:genetics; D005399:Fishes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D049878:Mytilus / Q000235:genetics; D010802:Phylogeny; D010932:Planarians / Q000235:genetics; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D029941:Fish Proteins; D053181:Caspase 8
keywords: FADD; caspase; exon shuffling; intron insertions; operon