ANRV306-IY25-19 ARI 11 February 2007 12:51 The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation Hyun Ho Park,1 Yu-Chih Lo,1 Su-Chang Lin,1 Liwei Wang,1 Jin Kuk Yang,1,2 and Hao Wu1 1Department of Biochemistry, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021; email: [email protected] 2Department of Chemistry, Soongsil University, Seoul 156-743, Korea Annu. Rev. Immunol. 2007. 25:561–86 Key Words First published online as a Review in Advance on death domain (DD), death effector domain (DED), tandem DED, January 2, 2007 caspase recruitment domain (CARD), pyrin domain (PYD), crystal The Annual Review of Immunology is online at structure, NMR structure immunol.annualreviews.org This article’s doi: Abstract 10.1146/annurev.immunol.25.022106.141656 The death domain (DD) superfamily comprising the death domain Copyright c 2007 by Annual Reviews. (DD) subfamily, the death effector domain (DED) subfamily, the Annu. Rev. Immunol. 2007.25:561-586. Downloaded from arjournals.annualreviews.org by CORNELL UNIVERSITY MEDICAL COLLEGE on 03/29/07. For personal use only. All rights reserved caspase recruitment domain (CARD) subfamily, and the pyrin do- 0732-0582/07/0423-0561$20.00 main (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfam- ily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular in- teractions mediated by them. By analyzing the potential molecular basis for the function of these domains, we hope to provide a com- prehensive understanding of the function, structure, interaction, and evolution of this important family of domains. 561 ANRV306-IY25-19 ARI 11 February 2007 12:51 INTRODUCTION: APOPTOSIS tory processes. As shown in the following sec- AND INFLAMMATION tion, these proteins are often involved in both caspase and NF-κB activation. Sometimes the Apoptosis is an orderly cellular suicide pro- same molecular complex is regulated to signal gram (1, 2) critical for the development and either cell death via caspase activation or in- homeostasis of a multicellular organism. Fail- flammation via kinase activation. ure to control apoptosis can lead to serious Because both apoptosis and inflammation diseases that threaten the existence of the or- are associated with many human diseases, ganism (3, 4). Biologically, apoptosis is highly studies in these areas have ultimate biological integrated with inflammation and host de- importance. The past decade has seen an ex- fense against intracellular pathogens such as plosion of biochemical and structural studies viruses. Because viruses depend on host cells of proteins involved in apoptotic and inflam- to replicate, the suicide apoptotic program is matory signaling. These structures and their often elicited in virally infected cells to re- interactions with partner proteins have re- move the viruses and to limit viral spread. On vealed the underlying molecular basis for the the opposing side, viruses often carry genes assembly of important signaling complexes that induce the host inflammatory processes, and for the regulation of apoptosis and in- which often suppress the cellular apoptotic flammation. This review focuses on the biol- program. ogy, structure, and function of the DD super- Apoptosis proceeds through characteristic family. For other apoptotic and inflammatory morphological changes (1, 2) that are depen- signaling modules, please see related recent dent on caspase activities. Caspases are cys- reviews (16–18). teine proteases that cleave specifically after aspartic-acid residues (5, 6). Because caspases are the executioners of apoptosis, they are the key players in apoptotic cell death. In con- THE DEATH DOMAIN (DD) trast, inflammatory processes often rely on SUPERFAMILY IN THE the activation of protein kinases. One impor- ASSEMBLY OF APOPTOTIC AND tant proinflammatory kinase is the IκB ki- INFLAMMATORY COMPLEXES nase (IKK) (7–10), which phosphorylates IκB, The DD superfamily is one of the largest leading to its degradation (11). This liberates and most studied domain superfamilies (19). the NF-κB transcriptional factors, resulting It currently comprises four subfamilies: the in their nuclear translocation and activation. death domain (DD) subfamily, the death ef- NF-κBs subsequently induce the transcrip- fector domain (DED) subfamily, the cas- tion of genes for immune and inflammatory pase recruitment domain (CARD) subfam- responses and for the suppression of apopto- ily, and the pyrin domain (PYD) subfamily Annu. Rev. Immunol. 2007.25:561-586. Downloaded from arjournals.annualreviews.org by CORNELL UNIVERSITY MEDICAL COLLEGE on 03/29/07. For personal use only. sis (12–14). (16). These proteins are evolutionarily con- On the molecular level, some protein fam- served in many multicellular organisms, in- ilies are involved in both apoptotic and in- cluding mammals, Drosophila, and Caenorhab- flammatory signaling. For example, whereas ditis elegans. In the human genome, there are caspases are generally apoptotic initiators and 32 DDs, 7 DEDs, 28 CARDs, and 19 PYDs effectors, a subclass of caspases is explicitly (16, 17). Perhaps as evidence of integration involved in proinflammatory responses. This with host apoptotic and inflammatory pro- includes caspase-1, which cleaves pro-IL-1β cesses, some viruses have acquired DD super- to IL-1β, leading to NF-κB activation and family sequences. For example, herpesviruses elicitation of proinflammatory responses (15). have DED-containing sequences that inhibit Proteins in the death domain (DD) superfam- cell death, and poxviruses have both DED- ily are also shared in apoptotic and inflamma- containing and PYD-containing sequences 562 Park et al. ANRV306-IY25-19 ARI 11 February 2007 12:51 TNFR-1 CRD CRD CRD CRD TM DD Nod1 CARD NOD LRR Fas CRD CRD CRD TM DD Nod2 CARD CARD NOD LRR p75 CRDCRD CRD CRD TM DD RIP2 Kinase CARD TRADD DD ICEBERG CARD FADD DED DD RIG-I CARD CARD Helicase domain RIP Kinase DD MDA5 CARD CARD Helicase domain MyD88 DD TIR MAVS CARD IRAKs DD Kinase Caspase-2 CARD Caspase Pelle DD Kinase ASC PYD CARD Tube DD NALP1 PYD NOD LRR CARD PIDD LRR ZU5 ZU5 ZU5 DD Caspase-1 CARD Caspase RAIDD CARD DD Caspase-5 CARD Caspase MALT1 DD Ig Ig Caspase Caspase-8 DED DED Caspase WD repeats Apaf-1 CARD NOD Caspase-10 DED DED Caspase WD repeats DARK CARD NOD c-FLIP DED DED Pseudo caspase CED-4 CARD NOD v-FLIPs DED DED Caspase-9 CARD Caspase MC159 DED DED CED-3 CARD Caspase PEA-15 DED Dronc CARD Caspase DEDD DED CARMA1 CARD PDZ SH3 GUK DEDD2 DED Bcl-10 CARD Figure 1 Domain organizations of selective proteins containing the DD superfamily domains. (Abbreviations: CARD, caspase recruitment domain; DD, death domain; DED, death effector domain; GUK, guanylate kinase-like; LRR, leucine-rich repeat; NOD, nucleotide-binding oligomerization domain; PYD, pyrin domain; TIR, Toll/interleukin-1 receptor; CRD, cysteine-rich domain; TM, transmembrane domain.) that interfere with host apoptotic and inflam- PYD-containing 1) PYD (27) (Figure 2). Al- matory responses to viral infection (20–23). In though all members of the DD superfamily some cases, the DD superfamily domain is the have this conserved structural fold, individual only motif present in these proteins. In most subfamilies also exhibit distinct structural and Annu. Rev. Immunol. 2007.25:561-586. Downloaded from arjournals.annualreviews.org by CORNELL UNIVERSITY MEDICAL COLLEGE on 03/29/07. For personal use only. cases, however, the DD superfamily domain sequence characteristics not shared with other is combined with domains of other subfami- subfamilies. lies or domains outside the DD superfamily A central paradigm common to both cas- (Figure 1). pase activation and NF-κB activation is the The unifying feature of the DD super- assembly of oligomeric signaling complexes family is the six-helical bundle structural fold in response to internal or external stimuli. In as first revealed by nuclear magnetic reso- a simplified view, these molecular complexes nance (NMR) structures of Fas DD (24), activate their effectors via proximity-induced FADD (Fas-associated death domain pro- autoactivation such as dimerization, prote- tein) DED (25), RAIDD (RIP-associated pro- olytic processing, and trans-phosphorylation. tein with a death domain) CARD (26), and The DD superfamily plays a critical role NALP1 (NACHT, leucine-rich repeat and in this assembly by participating in both www.annualreviews.org • Death Domain Superfamily 563 ANRV306-IY25-19 ARI 11 February 2007 12:51 death pathway. Members of the TNF su- perfamily of ligands are mostly trimeric and can be either membrane attached or solu- ble. They activate the TNF receptor super- family by ligand-induced receptor trimeriza- tion (28) and higher-order oligomerization (29). The intracellular regions of death re- ceptors contain DDs (30–32), upon which caspase-activating and NF-κB-activating sig- naling complexes are assembled. Researchers have shown that self-association of the DDs in these receptors is required for signal transduc- tion (33). Three different types of complexes may be assembled, one by the death receptor Fas and related receptors and the other two by the death receptor TNFR1 and related re- ceptors. For Fas, upon ligand activation, its DD recruits the FADD adapter protein via a ho- motypic interaction with the C-terminal DD of FADD (29, 34). FADD also contains an N-terminal DED that interacts homotypi- cally with the tandem DED in the prodomain of caspase-8 or -10 (35, 36). These interac- tions form the ternary death-inducing signal- ing complex (DISC), containing Fas, FADD, and caspase-8 or -10 (32). Recruitment of pro- caspases into the DISC initiates caspase prote- olytic autoprocessing (37–39). This liberates active caspase-8 or -10 into the cytoplasm to cleave and activate effector caspases such as Figure 2 self-association and other protein-protein in- caspase-3 and caspase-7, leading to a cascade Ribbon diagrams for teractions.