The apoptotic initiator caspase-8: Its functional ubiquity and genetic diversity during animal evolution

Kazuhiro Sakamaki, Kouhei Shimizu, Hiroaki Iwata, Kenichiro Imai, Yutaka Satou, Noriko Funayama, Masami Nozaki, Mamiko Yajima, Osamu Nishimura, Mayura Higuchi, Kumiko Chiba, Michi Yoshimoto, Haruna Kimura, Andrew Y. Gracey, Takashi Shimizu, Kentaro Tomii, Osamu Gotoh, Koji Akasaka, Tatsuya Sawasaki, David J. Miller

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3282-3301
Number of pages20
JournalMolecular biology and evolution
Issue number12
Publication statusPublished - 2014 Dec 1
Externally publishedYes


  • FADD
  • caspase
  • exon shuffling
  • intron insertions
  • operon

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics


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