The Role of Caspases in Development, Immunity, and Apoptotic Signal Transduction: Lessons from Knockout Mice

Abstract

The rapid discovery of a great number of caspases, together with multiple control points of their activation, proceeds well ahead of our knowledge of their physiological roles within the organism. There are still major gaps, but recent gene targeting of caspases provides us with several new and fundamental aspects of their physiological functions. The fact that different lines of KO mice exhibit preferential apoptosis defects rather than a global suppression of apoptosis indicates that caspases play a largely nonredundant apoptotic role in a tissue- and stimulus-dependent manner. Furthermore, despite compelling evidence for a key role of Casp8 and Casp9, the restricted phenotype of both Casp8- and Casp9-deficient mice suggests that other apical caspases must exist regulating apoptotic processes. Casp10, for instance, which is very similar in its structure to Casp8, has been shown to be recruited to death receptors (13xIn vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Fernandes-Alnemri, T, Armstrong, R.C, Krebs, J, Srinivasula, S.M, Wang, L, Bullrich, F, Fritz, L.C, Trapani, J.A, Tomaselli, K.J, Litwack, G, and Alnemri, E.S. Proc. Natl. Acad. Sci. USA. 1996; 93: 7464–7469Crossref | PubMed | Scopus (653)See all References, 72xFas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. Vincenz, C and Dixit, V.M. J. Biol. Chem. 1997; 272: 6578–6583Crossref | PubMed | Scopus (239)See all References). Although fibroblasts from Casp8 null mice are almost completely resistant to death receptor–mediated apoptosis, it cannot be excluded that Casp10, having little importance in fibroblasts, exerts crucial functions in other cell types. In addition, since certain cell types such as embryonic fibroblasts from Apaf1 KO mice are still considerably sensitive to a variety of apoptosis inducers, it is very likely that other yet undiscovered key regulators exist. We also have to be aware that the restricted phenotype of most KO mice may underestimate the role of the targeted caspases, because single caspases may substitute other family members. A major obstacle of most KO mice is their prenatal lethality, which precludes manifestations of caspase functions in the adult organism. Therefore, in future research, conditional disruption in a cell type–specific manner or in certain developmental stages will be required to elucidate more precisely the in vivo functional significance of individual caspases in development, immune functions, and pathological forms of apoptosis.*To whom correspondence should be addressed (e-mail: kso@uni-muenster.de).†Present address: Division of Cell Biology, University of Munster, Rontgenweg 21, D-48149 Munster, Germany.