Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Clearance of Dying Cells in Healthy and Diseased Immune Systems Anti-inflammatory functions of the “apoptotic” caspases David Wallach, Tae-Bong Kang, Akhil Rajput, Jin-Chul Kim, Konstantin Bogdanov, Seung-Hoon Yang, and Andrew Kovalenko Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel Address for correspondence:Dr. David Wallach, Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel. d.wallach@weizmann.ac.il The two main known functions of the caspases act antagonistically in regulating inflammation. “Inflammatory” caspases trigger inflammation by catalyzing the processing of IL-1β precursors and other proinflammatory cytokines. In contrast, “apoptotic” caspases safeguard against the triggering of inflammation by imposing a cell-death form that withholds release of alarmins by dying cells and dictates generation of anti-inflammatory mediators. These antagonizing functions are exerted by evolution-related mechanisms. Studies of the function of caspase-8, an enzyme- mediating apoptotic cell-death induction in response to TNF-family ligands, reveal that it blocks inflammation in additional ways. One way is by restricting activation of the RIG-I complex by foreign ribonucleic acid. Chronic skin inflammation in mice with caspase-8–deficient epidermis is associated with constitutive activation of the RIG-I complex in keratinocytes. This activation is apparently prompted by nucleic acids released from epidermal cells that disintegrate during cornification, and becomes chronic because it is not restricted by caspase-8. Keywords: apoptosis; caspase; inflammation; IRF3; necrosis; RIG-I “Inflammatory” and “apoptotic” caspases The caspase family of cysteine proteases is known mainly for two distinct activities. One is triggering of inflammation, which occurs through the process- ing of precursors of inflammatory cytokines, such as interleukin (IL)-1, known to be mediated in humans by caspases 1, 4, and 5 (and antagonized by caspase-12). The other is induction of apoptotic death, with the participation of caspases 2, 3, 6, 7, 8, 9, and 10. 1,2 Despite the differing spectra of their protein sub- strates and the marked differences in the functional consequences of cleavage of their substrates, the ini- tiator caspases of these two groups share similar structures and similar mechanisms of activation. In both groups, activation is initiated at a distinct N- terminal region of the protein—the “prodomain”— which comprises one of two related structural mo- tifs of the “death-fold” group: either the caspase re- cruitment domain (CARD) domain or, in the case of caspase-8 and -10, the death-effector domain. In both groups, these prodomain motifs initiate aggre- gation and hence activation of the caspases by bind- ing, through homo-association of death-fold mo- tifs, to an oligomer of upstream regulatory proteins. In the case of the activation of caspases that medi- ate death in response to intracellular inducers (the intrinsic cell-death pathway), structural similarities to the “inflammatory” caspases extend beyond the caspases themselves. Apoptotic protease activating factor 1 (Apaf1), the adapter protein that im- poses generation of the “apoptosome”—the molec- ular complex that accommodates the activation of caspase-9, which initiates the intrinsic cell-death pathway—is structurally and evolutionarily related to the NLR (nucleotide-binding domain, leucine rich) proteins, the adapters that bring together the inflammasome complexes in which the inflamma- tory caspases are activated. 1,2 In early essays about the caspases, their two activi- ties known at that time—triggering of inflammation and initiation of apoptosis—were presented as un- related entities, and the fact that in the course of evolution members of the same enzyme family had become involved in both activities was assumed to doi: 10.1111/j.1749-6632.2010.05742.x Ann. N.Y. Acad. Sci. 1209 (2010) 17–22 c  2010 New York Academy of Sciences. 17