ANRV306-IY25-19 ARI 11 February 2007 12:51

The Superfamily in Intracellular Signaling of 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), (DED), tandem DED, January 2, 2007 recruitment domain (CARD), (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 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.

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INTRODUCTION: APOPTOSIS tory processes. As shown in the following sec- AND 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 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 . 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. are cys- reviews (16–18). teine 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 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

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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 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, -rich repeat; NOD, nucleotide-binding oligomerization domain; PYD, pyrin domain; TIR, Toll/interleukin-1 ; CRD, -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-. 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

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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 -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. Some examples of these impor- each subfamily of the of events in apoptotic cell death (5). DD superfamily: tant signaling complexes are presented below For TNFR1, upon ligand stimulation, its (a) Fas death domain (Table 1). Interestingly and perhaps surpris- DD recruits the multifunctional TRADD (DD), (b) FADD ingly, interactions within the superfamily are (TNFR1-associated death domain protein) 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. death effector almost all homotypic in that only domains adapter protein via the DD interaction. domain (DED), within the same subfamily interact with each TRADD in turn recruits RIP (receptor- (c) RAIDD caspase recruitment domain other. interacting protein) via the DD interaction (CARD), and at its C-terminal DD and TNF receptor– (d ) NALP1 pyrin associated factors (TRAFs) via its N-terminal domain (PYD). The Death Receptor Signaling domain, forming the membrane-bound com- Pathways: The Death-Inducing plex I for IKK and NF-κB activation. In a sec- Signaling Complex, Complex I, ond step, TRADD dissociates from TNFR1 and Complex II and associates with FADD and caspase-8 to Death receptors form a subfamily of the form a cytoplasmic complex II for caspase ac- (TNF) receptor su- tivation (40). As in the DISC, both DD:DD perfamily. They mediate the extrinsic cell and DED:DED interactions are important for

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Table 1 Selective signaling complexes involving the DD superfamily Signaling complexes Domains Protein components DISC DD, DED Fas, FADD, caspase-8 or -10 Complex I DD TNFR1, TRADD, RIP, TRAF Complex II DD, DED TRADD, RIP, FADD, caspase-8 or -10 CARD Apaf-1, cytochrome c, ATP/dATP, caspase-9 PIDDosome DD, CARD PIDD, RAIDD, caspase-2 TLR/IL-1 R complex DD MyD88, TIRAP, IRAKs, TRAF6 Nod pathway CARD Nod1 or Nod2, RIP2, caspase-1 RIG pathway CARD RIG-I or MDA5, MAVS TCR/BCR signaling CARD CARMA1, Bcl-10, MALT1 Inflammasome PYD NALP1, ASC, caspase-1, caspase-5

DD, death domain; CARD, caspase recruitment domain; DED, death effector domain; PYD, pyrin domain.

the assembly of complex II. The regulated as- DD (55–58). Patients with ALPS have chronic sembly of complex I and complex II may un- enlargement of the spleen and lymph nodes, derlie TNF’sability to induce either cell death various manifestations of autoimmunity, and or cell survival under different cellular con- elevation of a normally rare population of T texts. lymphocytes. Caspase activation by both the DISC and complex II is inhibited by FLIPs (FLICE-like inhibitory proteins), a family of cellular and The Intrinsic Apoptosis Pathway: viral tandem DED-containing proteins that The Apoptosome interact with FADD (41). Cellular FLIPs (c- The intrinsic pathway of apoptotic cell death FLIPs), comprising the long and short iso- is induced in a mitochondria-dependent man- forms (c-FLIP-L and c-FLIP-S), are tightly ner in response to intracellular insults. The regulated in expression in and may be CARD-containing protein Apaf-1 forms the involved in controlling both T cell activation central platform of a molecular complex and death (41–49). v-FLIPs (viral FLIPs) ap- known as the apoptosome for caspase activa- pear to have evolved to inhibit apoptosis of tion in this pathway (59, 60). Apaf-1 comprises virally infected host cells and are present in an N-terminal CARD, a central nucleotide- the poxvirus molluscum contagiosum as binding oligomerization domain (NOD), and proteins MC159 and MC160 (20–22, 50, 51) a C-terminal (tryptophan–aspartic acid) WD and in γ-herpesviruses (20–22, 41, 52). repeat domain. Upon mitochondrial leakage, 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. Deregulation of death receptor signaling cytochrome c, which normally resides at the is related to many human diseases. Most intermembrane space of the mitochondria, is notably, defective Fas signaling manifested released to the cytosol. The interaction of cy- as defective function of the DISC underlies tochrome c with the WD repeat domain of the human genetic disease autoimmune lym- Apaf-1 presumably opens up the Apaf-1 struc- phoproliferative syndrome (ALPS) (53, 54). ture, leading to an ATP- or dATP-dependent When lymphocytes from patients with ALPS oligomerization of Apaf-1 to form the apopto- are cultured in vitro, they are resistant to some. The apoptosome then recruits caspase- apoptosis as compared with cells from healthy 9 via the CARD interaction between Apaf-1 controls. Most patients with ALPS have mu- and caspase-9. tations in the Fas gene, and more than 70 mu- In Drosophila, the related apoptosome is tations have been mapped to its intracellular formed by the Apaf-1 ortholog Dark and the

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caspase-9 ortholog Dronc (61). In C. elegans, the IL-1 receptor and most TLRs recruit the Apaf-1 ortholog is CED-4, which does not MyD88, TLR2 and TLR4 also recruit an- contain an analogous C-terminal WD repeat other TIR-containing protein, TIRAP (69). domain for cytochrome c interaction. Instead, MyD88 contains both a DD and a TIR do- CED-4 is constitutively active but is kept in main, and it in turn recruits IL receptor– check by an interaction with CED-9, a Bcl-2 associated kinases (IRAKs)—which include ortholog, which prevents CED-4 oligomer- IRAK1, IRAK2, IRAKM, and IRAK4—via ization. Egl-1 is induced to antagonize CED- a DD interaction. IRAKs contain a DD 9 upon apoptosis. CED-4 then oligomerizes and a serine/threonine (Ser/Thr) kinase do- to form the worm apoptosome, and interacts main. IRAKs subsequently recruit TRAF6 for and activates CED-3, the caspase ortholog, NF-κB activation (70). In Drosophila, a het- via a CARD interaction (61). erotrimeric complex of MyD88, Tube, and Pelle mediates the orthologous Toll pathway (71), which is important for both immunity PIDD-Mediated Responses to DNA against fungal infection (72) and for dorsoven- Damage: Caspase-2 Activation by the tral patterning (73). Whereas Pelle is the func- PIDDosome and RIP-Mediated tional ortholog of IRAK, Tube is an adapter NF-κB Activation protein. MyD88, Tube, and Pelle all contain In response to genotoxic stress, the DD- a DD and assemble via DD interactions. containing and p53-inducible protein PIDD mediates both caspase-2 and NF-κB activa- tion. Caspase-2 is an evolutionarily conserved Antigen Receptor-Induced NF-κB initiator caspase with a CARD prodomain Activation Pathway (62). The caspase-2 activation pathway in- NF-κB activation by T cell and B cell re- volves the formation of a ternary complex ceptors (TCRs and BCRs) is initiated by termed the PIDDosome (63, 64), which com- receptor-associated tyrosine kinases of the prises proteins PIDD (65), RAIDD (66), and Src and Syk family and a protein kinase C caspase-2 and is assembled via the DD in- (PKC) family member (PKC-θ or PKC-β), teraction between PIDD and RAIDD and respectively (74). Upon TCR or BCR ac- the CARD interaction between RAIDD and tivation, the PKC isoforms translocate to caspase-2. Accumulating data demonstrate membrane-bound large molecular complexes that caspase-2 acts upstream of the mitochon- in lipid rafts. Although the exact connec- dria to initiate apoptosis (67). Upon geno- tion to PKC-θ and PKC-β remains unre- toxic stress, PIDD also recruits the DD- solved, a three-molecule complex containing containing kinase RIP,which in turn interacts CARMA1, Bcl-10, and MALT1appears to act with the IKK complex for NF-κB activation downstream to activate IKK. CARMA1 con- 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. (68). Therefore, it appears that PIDD acts as tains an N-terminal CARD, followed by a a molecular switch to control life and death coiled-coil domain, a PDZ domain, an SH3 after DNA damage. domain, and a C-terminal guanylate kinase- like (GUK) domain (75, 76). The PDZ, SH3, and GUK domains in CARMA clas- The NF-κB Activation Pathway of sify it into the membrane-associated guany- the IL-1 Receptor and Toll-Like late kinase family, which plays important Receptors roles in regulating the interface between In the mammalian interleukin (IL)-1 receptor membrane components and cytoskeletal pro- and Toll-likereceptor (TLR) pathway, the in- teins. CARMA1 interacts with Bcl-10, a pro- tracellular TIR domain of these receptors re- tein with an N-terminal CARD and a C- cruits TIR-containing adapters (69). Whereas terminal Ser/Thr-rich region, via the CARD

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interaction (77). MALT1 is a DD-containing In a presumably similar pathway mediated , which contains an N-terminal by Nod2, intracellular bacterial lipopolysac- DD, two central immunoglobulin-like do- charides are recognized and NF-κB activation mains, and a C-terminal caspase-like domain is induced, leading to innate immunity and for which catalytic activity has not been shown bacterial clearance (85, 86). Nod2 is crucial (78). The C-terminal Ser/Thr-rich region of for immunity against in the gastroin- Bcl-10 and the immunoglobulin-like domains testinal tract, as a loss-of-function mutation in of MALT1are responsible for the recruitment Nod2 underlies a susceptibility to Crohn’sdis- of MALT1 by Bcl-10. ease, a chronic inflammatory disorder of the How the CARMA1, Bcl-10, and MALT1 gut (86). complex activates IKK is still unclear. One Researchers have identified several nega- possible model is that this complex further re- tive regulators of caspase-1 activation. In par- cruits the heterodimeric complex of caspase- ticular, both ICEBERG and COP are CARD- 8 and c-FLIP-L, which assists caspase-8 ac- containing proteins. They interact with tivation and in turn is cleaved by activated either caspase-1 or RIP2 CARDs and inhibit caspase-8 to an intermediate p43 form (79). caspase-1 activation by RIP2 (87, 88). This in- The p43 form of c-FLIP-L efficiently acti- hibition may provide a negative feedback loop vates NF-κB via the TRAF pathway, and both to terminate inflammatory responses. c-FLIP and caspase-8 are required for the survival and proliferation of T cells follow- ing TCR stimulation (79). MALT1 contains Intracellular Viral Infection Sensing potential TRAF6-binding sites and activates and Signaling for Antiviral Immunity: IKK via the TRA6-TAK1 pathway as well The RIG-Like Helicase Pathway (80). Similar to Nods, RIG-like form an- other family of intracellular pathogen pattern sensors whose primary target is virally derived Intracellular Bacterial Sensors: double-stranded (ds) RNA (89). Proteins in The Nod Pathway this family, such as RIG-I and MDA5, con- CARD-containing proteins known as Nods tain tandem CARDs at the N-terminal re- participate in sensing intracellular pathogens gion and a helicase domain with the DExD/H and eliciting innate immunity against these motif at the C-terminal region. Presumably, pathogens. For example, Nod1 contains an binding of dsRNA to the helicase domain of N-terminal CARD, a central NOD, and a C- RIG-I or MDA5 would cause a conforma- terminal leucine-rich repeat (LRR) domain tional change that exposes the tandem CARDs (81). This domain architecture is similar to for recruiting downstream adapter proteins. the Apaf-1 protein involved in apoptosome Several groups independently identified one 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. formation and caspase-9 activation. Upon in- such adapter recently, and it was therefore teraction with ligands on intracellular bacteria named independently MAVS, Cardif, IPS-1, via its LRR, Nod1 presumably oligomerizes and VISA (90–93). MAVS is critical for medi- through its NOD. The N-terminal CARD of ating NF-κB activation and the activation of Nod1 interacts with RIP2, which contains an IRF3/7 to produce antiviral type I interferon N-terminal Ser/Thr kinase domain and a C- (94, 95). It contains an N-terminal CARD that terminal CARD (82). RIP2 in turn recruits interacts with RIG-I or MDA5 through a ho- the IKK complex for NF-κB activation (83). motypic CARD interaction. The C-terminal In addition to the IKK complex, RIP2 can also region of MAVS possesses a mitochondrial interact with caspase-1 via its CARD domain, targeting sequence that anchors MAVS to resulting in the cleavage and activation of pro- the outer membrane of mitochondria, which IL-1β (84). is critical for its function (90). Although

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Table 2 Nuclear magnetic resonance (NMR) and crystal PYD and a C-terminal CARD (102). NALP1 structures in the DD superfamily interacts with ASC via the PYD and with Technique Reference(s) caspase-5 via the CARD. These proteins, to- ∼ Fas DD NMR 24 gether with caspase-1, form the 700-kDa p75 NGFR DD NMR 104 inflammasome for caspase-1 activation (99). FADD DD NMR 106, 107 Activated caspase-1 cleaves and activates pro- TNFR1 DD NMR 103 IL-1β, leading to NF-κB activation and elic- itation of innate immunity. IRAK4 DD Crystallography 105 RAIDD DD Crystallography 108 Tube DD:Pelle DD Crystallography 109 STRUCTURAL AND + FADD DED DD NMR 119 BIOCHEMICAL STUDIES OF FADD DED NMR 25 THE DEATH DOMAIN PEA-15 DED NMR 118 SUBFAMILY MC159 tandem DED Crystallography 116, 120 Apaf-1 CARD:caspase-9 CARD Crystallography 124 Death Domain Structures Apaf-1 CARD Crystallography 122 Currently, structures of six isolated DDs are + Apaf-1 CARD NOD Crystallography 123 available, which include the NMR structures RAIDD CARD NMR 26 of Fas DD, FADD DD, TNFR1 DD, and ICEBERG CARD NMR 87 the p75 NGFR (nerve growth factor receptor) CED-4:CED-9 Crystallography 125 DD and the crystal structures of IRAK4 DD ASC PYD NMR 128 and RAIDD DD (24, 103–108) (Table 2). Be- NALP1 PYD NMR 27 cause these domains are involved in protein- protein interactions and have a tendency to DD, death domain; CARD, caspase recruitment domain; DED, death effector aggregate, many of these structures were de- domain; PYD, pyrin domain. termined under nonphysiological conditions, such as extreme pH and/or with deaggregat- ing mutations. Whereas all these DDs ex- RIG-I and MDA5 share the same domain hibit the six-helical bundle fold, variations ex- structure, they appear to detect different ist in the length and direction of the helices viruses (96, 97). The third member of the (Figure 3a). Because of the low sequence ho- RIG-like helicase family, LGP2, is devoid of mology among DDs, the surface features of the CARD and prevents activation of antivi- these DDs are also entirely different, which ral responses, most likely through competitive may be responsible for their specificity in binding to dsRNA (95, 98). protein-protein interactions. 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. The Caspase-1 Activation Pathway: DD:DD Interaction The Inflammasome Despite the immense biological importance of The PYD-containing proteins NALP1 and DDs, only one structure of a DD:DD complex ASC (apoptosis-associated speck-like protein is available, which is the crystal structure of containing a CARD) participate in the for- the monomeric Pelle DD:Tube DD complex mation of the inflammasome for caspase- (109) (Figure 3b). Regardless of the details 1 activation (99). NALP1 contains an N- of the interaction, the biggest surprise is per- terminal PYD, a central NOD presumably haps the asymmetry of the interaction, con- involved in oligomerization, an LRR region, sidering our understanding of homotypic in- and a C-terminal CARD (100, 101). ASC is teractions. The first interface involves the H4 an adapter protein containing an N-terminal helix and the following loop of Pelle and the

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Figure 3 Structural features of DDs and DD:DD interactions. (a)A stereo diagram of the superimposed known DD structures. Colors are as shown at right. (b) Pelle DD:Tube DD complex. Colors as shown. (c) Hypothetical models for a threefold symmetric Fas DD:FADD DD 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. complex. In one model, FADD DD interacts with one Fas DD only. In the other model, FADD DD interacts with two adjacent Fas DD molecules.

H1-H2 corner, H6, and the preceding loop the second interface and contributes signifi- in Tube. Most strikingly, the C-terminal tail cantly to the interaction (109). Whereas many of Tube wraps around a groove formed by the charged residues at the first interface (such as H4-H5 and H2-H3 hairpins of Pelle to form E50 of Tube and R35 of Pelle) are involved

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in the interaction, three large hydrophobic interacts only weakly with full-length FADD residues (I169, L171, and L173) on the C- in the absence of the third component of terminal tail of Tube dominate the second the DISC (116), the pulldown of full-length interface. FADD by GST-Fas DD appeared to be Mutational studies based on the crystal efficient (117). structure of Tube showed that the MyD88 DD:TubeDD interaction uses a different sur- face of the Tube DD (71, 110). Therefore, STRUCTURAL AND Tube acts as the bridge between MyD88, BIOCHEMICAL STUDIES OF which interacts directly with Toll and Pelle, THE DEATH EFFECTOR which signals downstream for the nuclear DOMAIN SUBFAMILY translocation and activation of the NF-κBor- Death Effector Domain Structures tholog Dorsal, the key event in dorsoventral patterning. Currently, four DED structures are available, The structural basis of DD:DD inter- which include the NMR structures of FADD actions involved in death signaling (such DED (25) and PEA-15 DED (118), and the as those in the Fas DD:FADD DD com- DED1 and DED2 structures from the crystal plex, the TRADD DD:FADD DD complex, structure of the tandem DED of MC159 (116) and the PIDD DD:RAIDD DD complex) re- (Figure 4a)(Table 2). The NMR structure of mains largely unresolved. Although no solid FADD DED is also known in the context of its experimental evidence is available, the Fas full-length structure comprising both a DED DD:FADD DD complex is likely to be and a DD (119). Whereas FADD is a com- trimeric, most likely with Fas possessing ponent of the DISC, PEA-15 appears to par- the self-oligomerization surface (Figure 3c). ticipate in mitogen-activated protein (MAP) Therefore, the complex might comprise at kinase activation through a nonhomotypic in- least two interfaces, a self-oligomerization teraction with the kinase extracellular signal- surface and a Fas DD:FADD DD interac- regulated kinase (ERK) (118). MC159 is a tion surface. This conjecture of multiple in- v-FLIP from a poxvirus that inhibits caspase teraction surfaces in these complexes is sup- activation at the DISC (116). As predicted and ported by mutational data, which showed wide consistent with their assignment to the DED spreads of residues important for binding subfamily, the structures of FADD DED, and/or function on the surfaces of Fas (111), PEA-15 DED, and MC159 DED2 show the FADD (112), TRADD (113), and TNF-R1 conserved six-helical bundle fold of the DD (114). Alternatively, the Fas DD:FADD DD superfamily and are more similar to each other complex may be constructed from the two than to other members of the DD superfamily types of interfaces observed in the Pelle (Figure 4b). 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. DD:Tube DD complex and in the Apaf-1 In contrast, the structure of MC159 DED1 CARD:caspase-9 CARD complex (see below) showed that it is structurally more divergent (115). This arrangement, however, does not from the other known DED structures (116, generate threefold symmetry. 120). In particular, helix H3 is missing and re- Controversial data exist on the proposed placed by a short loop connecting helices H2 interaction between Fas DD and FADD DD. and H4. Two additional helices are present, Whereas in vitro reconstitution showed that helix H0 at the N terminus and helix H7, Fas DD interacts strongly with FADD DD which brings the chain to the beginning of (116), an independent experiment showed DED2. Only approximately half the residues that GST-Fas DD failed to pull down FADD in DED1 were aligned within 3 AinC˚ α dis- DD (117). In addition, whereas the same tance to DED2, FADD DED, and PEA-15 in vitro reconstitution showed that Fas DD DED.

570 Park et al. ANRV306-IY25-19 ARI 11 February 2007 12:51 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.

Figure 4 Structural features of death effector domains (DEDs) and tandem DEDs. (a) A ribbon diagram of the tandem DED structure of MC159. (b) A stereo diagram of superimposed known DED structures. (c) Charge triad motif. (d ) Surface features of MC159, showing the hydrophobic patch and charge triad surfaces that are conserved in almost all DEDs. (e) MC159 DED1:DED2 interaction. Diagrams c, d, and e are modified from Yang et al. (116).

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Surface Features DED:DED Interaction as Seen in Two prominent conserved surface features are Tandem Death Effector Domains present on DEDs, distinguishing DEDs from The structure of MC159 revealed the first other members of the DD superfamily. The glimpse of a DED:DED interaction (116). In- first feature is a conserved hydrogen-bonded stead of beads on a string, DED1 and DED2 charge triad revealed by the high-resolution interact with each other intimately to form structure of MC159 (116). The charge triad a rigid, dumbbell-shaped structure. The two is formed by the E/D-RxDL motif and in- DEDs are related approximately by a transla- volves the arginine and aspartate residues in tion across the contact interface, so one side the RxDL motif in helix H6 and the preced- of DED1 is contacting the equivalently oppo- ing loop, and an acidic residue in helix H2. site side of DED2. The translational relation- Extensive hydrogen-bonding interactions are ship between DED1 and DED2 is made possi- observed among the charged side chains with ble by helix H7 of DED1. The DED1:DED2 the arginine residue situated between the two interface is extensive, burying approximately acidic residues (Figures 4c,d ). These hydro- 1380-A˚ 2 surface area. gen bonds likely help to maintain a precise The interaction at the DED1:DED2 in- organization of the side chains, which may terface is mostly hydrophobic, mediated by be functionally important. They may possi- helices H2 and H5 of DED1 and helices H1 bly play a local structural role in maintaining and H4 of DED2 (Figure 4e). There are a to- the conformation of this region of the DEDs. tal of 195 interfacial atomic contacts, among The charge triad is highly conserved in most which 117 are between nonpolar atoms. The single and tandem DEDs. With the exception H1 and H4 surface of DED2 is equivalent to of the p75 DD, this motif is not present in the nonconserved hydrophobic patch identi- other members of the DD superfamily, sug- fied in the FADD DED structure on the oppo- gesting it is a characteristic feature of DEDs site side of the conserved hydrophobic patch, alone. As shown below, this surface may be and this surface does not appear to be im- used for FADD DED self-association and for portant in FADD signaling (25). The interfa- the interaction of FADD DED with MC159 cial residues are mostly conserved in tandem and MC160. DEDs, especially those that are completely The second surface feature is the con- buried at the DED1:DED2 interface and that served hydrophobic patch formed mostly by contribute large surface areas, such as F30, residues on H2 (Figure 4d ). Investigators L31, F92, L93, and R97. This suggests that first observed this feature in the NMR struc- all known tandem DEDs form a rigid compact ture of FADD DED (25) and later showed structure similar to MC159. This interaction it to be conserved in most tandem DEDs between DED1 and DED2 differs from both

Annu. Rev. Immunol. 2007.25:561-586. Downloaded from arjournals.annualreviews.org the known Pelle DD:Tube DD interaction

by CORNELL UNIVERSITY MEDICAL COLLEGE on 03/29/07. For personal use only. as well (116). In caspase-8, caspase-10, c- FLIP, and herpesvirus v-FLIPs, the two cen- (see above) and the Apaf-1 CARD:caspase-9 tral residues at this patch are strictly identi- CARD interaction (see below). cal with those in FADD DED. In MC159 and MC160, these two residues are still hy- drophobic but are replaced by conserved sub- FADD Death Effector Domain: stitutions. As shown below, this surface is used Self-Association and Interaction with extensively in DED:DED interactions, such Tandem Death Effector Domains as the MC159 DED1:DED2 interaction and There are two main functions of FADD DED: the interaction of FADD DED with caspase- self-association and interaction with tandem 8, caspase-10, c-FLIP, and herpesvirus DED proteins such as caspase-8 and MC159. v-FLIPs. Investigators have recently shown that FADD

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DED-mediated self-association is important passing its conserved charge triad on DED1 for the signaling competency of the DISC (116). Conversely, the charge-triad region of (117, 119, 121). Two separate regions of FADD DED appears to be important for both FADD DED, however, appear to be impor- its interaction with MC159 (116) and for its tant for this self-association. The first region self-association (121). MC159 thus interferes is the charge triad region of FADD DED with FADD self-association. Because FADD (121) and the other region is the hydropho- self-association is important for DISC clus- bic patch of FADD DED (117, 119). For the tering and signaling, MC159 inhibits DISC- latter, the self-association interface has to be mediated caspase activation. close to or at the caspase-8 interaction sur- These studies show that tandem DEDs are face (117, 119). One of the mapped FADD divided into two classes with regards to in- self-association interfaces may only indirectly teraction with FADD DED, those that are affect FADD self-association because of struc- MC159-like (including MC159 and MC160) tural alteration or another aspect of the FADD and those that are caspase-8-like (includ- function. ing caspase-8, caspase-10, c-FLIP, and her- The structure of MC159 provided a tem- pesvirus v-FLIPs). The former do not com- plate for all tandem DED proteins, which pete with caspase-8 recruitment to FADD and include caspase-8, caspase-10, c-FLIP, her- likely inhibit caspase activation via disruption pesvirus v-FLIPs, and the poxvirus v-FLIPs of FADD self-association. In contrast, the lat- MC159 and MC160 (116). Structure-based ter directly compete with caspase-8 recruit- sequence analysis and mutagenesis divided ment and therefore caspase activation at the tandem DEDs into two subclasses with re- DISC. gard to their mode of interaction with FADD DED. First, sequence analysis showed that the two core residues at the hydrophobic patch STRUCTURAL AND are strictly identical in FADD DED and tan- BIOCHEMICAL STUDIES dem DEDs, including caspase-8, caspase-10, OF THE CARD SUBFAMILY c-FLIP, and herpesvirus v-FLIPs. Mutational CARD Structures studies of FADD DED showed that this hy- drophobic patch is involved in caspase-8 re- CARD-containing proteins may be classified cruitment (25). Conversely, mutations on the into two classes: those at the prodomains of conserved hydrophobic patch of DED2 of caspases and those that act as adapters in caspase-8 also abolished the interaction of the assembly of apoptotic and inflammatory caspase-8 with FADD. This suggests a mutual signaling complexes. Currently, NMR struc- hydrophobic FADD DED:caspase-8 tandem tures are available for RAIDD CARD (26) and DED interaction (116). Similarly, c-FLIP and ICEBERG CARD (87). A crystal structure 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. herpesvirus v-FLIPs compete with caspase-8 is available for the isolated CARD of Apaf-1 recruitment to the DISC and interact with (122). In addition, the CARD structure of FADD DED similarly using the hydrophobic Apaf-1 is available in the context of the en- patch. tire N-terminal fragment of Apaf-1 contain- Second, consistent with the lack of strict ing the CARD and the NOD (123) and in conservation on the hydrophobic patch, mu- a complex with the caspase-9 CARD (124). tations on the exposed hydrophobic patch The structure of CED-4 CARD is available of MC159 on DED2 did not affect its in- as a complex of CED-4 and CED-9 (125) teraction with FADD DED. Instead, muta- (Table 2). tional studies on a large number of exposed Although the topology of these CARDs residues of MC159 showed that MC159 in- is identical with the conserved six-helical teracts with FADD DED via a region encom- bundle fold of the DD superfamily, the

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structure of CARDs is unique in that helix Apparent Lack of Self-Association H1 tends to be either bent or broken into of CARDs two closely separated H1a and H1b helices. In Unlike DDs and DEDs, whether CARDs also addition, the orientations and lengths of sev- self-associate is presently unclear. In the EM eral helices may be somewhat different among structure of the apoptosome, the CARD of the different CARDs (Figure 5a). Superposi- Apaf-1 appears to form a ring near the cen- tion of the Apaf-1 CARD structures in isola- ter of the assembly (126). In the presence of tion, in complex with caspase-9 CARD, and in full-length caspase-9, even the isolated Apaf- the context of its NOD domain shows there 1 CARD appears to undergo some level of is limited structural plasticity in this domain oligomerization (127). However, the isolated (Figure 5b). One important feature is that the Apaf-1 CARD and the complex of Apaf-1 surfaces of these CARDs are invariantly polar- CARD:caspase-9 CARD are both monomeric ized with both basic and acidic surfaces, which (122, 124). The CARDs, at least those present may be used for protein-protein interactions with an oligomerization NOD and those at (Figure 5c). the prodomains of caspases, may not possess the ability for stable self-association but rather may be mostly involved in interactions with CARD:CARD Interaction other CARDs. The crystal structure of the complex between Apaf-1 CARD and caspase-9 CARD pro- STRUCTURAL AND vides the only structure of a CARD:CARD BIOCHEMICAL STUDIES complex (124) (Figure 5d ). The interaction OF THE PYD SUBFAMILY is mediated by the mutual recognition of the slightly concave surface of caspase-9 The recent NMR structures of the NALP1 CARD formed by the positively charged PYD (27) and the ASC PYD (128) provided H1a, H1b, and H4 helices and the convex the definitive evidence that PYDs should be surface of Apaf-1 CARD formed by the a subfamily of the DD superfamily (129) negatively charged H2 and H3 helices. Three (Figure 6a)(Table 2). The structural infor- positively charged residues in caspase-9 mation is consistent with previous suggestions CARD (R13, R52, and R56) and two neg- based on sequence alignments and secondary atively charged residues in Apaf-1 CARD structure predictions (130–132). Despite hav- (D27 and E40) are crucial for this interaction ing the classical six-helical bundle fold of the (124). Whereas this study confirmed the DD superfamily, PYDs have an altered H3. ionic nature of the Apaf-1 CARD:caspase-9 In the case of the PYD from NALP1, H3 CARD interaction (Figure 5c), it re- is completely replaced by a flexible loop. For 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. mains undetermined whether this holds the PYD from ASC, only a short helix of four true for other CARD:CARD interactions, residues remains, which is coupled with a long such as the ICEBERG:caspase-1 and the flexible loop preceding the helix. Whether RAIDD:caspase-2 interactions. this region rearranges to form a more

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→

Figure 5 Structural features of CARDs and CARD:CARD interactions. (a) A stereo diagram of superimposed known CARD structures. (b) Superimposed Apaf-1 CARD structures when determined alone, in complex with caspase-9, and in WD-deleted Apaf-1. (c) Surface features of CARDs, showing the charged surfaces. Two orientations are shown, one similar to the caspase-9 interaction surface of Apaf-1 (left) and the other similar to the Apaf-1 interaction surface of caspase-9 (right). (d) Apaf-1 CARD:caspase-9 CARD structure.

574 Park et al. ANRV306-IY25-19 ARI 11 February 2007 12:51 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.

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protein-protein interactions in the DD su- perfamily (133, 134), the PYD:PYD inter- actions could be significantly different from classical modes of interactions in the DD superfamily. Although presently the PYD subfamily is the least well characterized of the four sub- families, it is clear that similar to other sub- families, proteins with PYDs are involved in inflammation, apoptosis, and NF-κB signal- ing such as the formation of the inflamma- some (99, 135). The mode of PYD:PYD in- teractions is presently completely unknown, but molecular modeling studies suggest the involvement of charged residues and electro- static interactions (Figure 6b). Acidic residues from H1 and H4 may interact with basic residues from H2 and H3 or the equivalent loops (128). In addition, site-directed muta- tional studies have suggested that H2, H3, and H4 (but not H1) are involved in ASC self- association (136). Researchers have implicated hereditary mutations in some genes of the PYD subfam- ily in a number of hyperinflammatory fever syndromes, such as the Muckle-Wells syn- drome and the familial Mediterranean fever, supporting the role of these proteins in reg- ulating inflammatory responses (137, 138). One familial Mediterranean fever–associated mutation is located at the equivalent H3 re- gion of the PYD (139), and another known mutation is located at H6 (140). These muta- tions possibly may either disrupt a PYD:PYD interaction required for negative regulation of inflammation or are gain-of-function mu- 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. tations of a PYD:PYD interaction required for proinflammatory responses. The molecu- Figure 6 lar basis of PYD:PYD interactions and disease Structural features of pyrin domains (PYDs). (a) A stereo diagram of mutations will have to wait for more structural superimposed PYDs: NALP1 PYD and ASC PYD. ( ) Electrostatic b studies. surface features of PYDs: the two opposite sides of NALP1 (left) and the two opposite sides of ASC (right).

extended H3 upon binding to a partner is un- Structural Comparisons Among known but is a possibility. The flexible, elon- the Homotypic Interactions gated loop preceding or at H3 seems to be Altogether, three homotypic complex struc- a common feature in many PYD sequences. tures in the DD superfamily are known: the Because H3 seems to play a critical role in Pelle DD:TubeDD complex (109), the Apaf-1

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CARD:caspase-9 CARD complex (124), and the DED1:DED2 interaction in the tandem DED of MC159 (116, 120). These structures raise the question of whether there are con- served modes of interaction common to all members of the DD superfamily. This ques- tion is especially interesting because of a re- cent proposition that perhaps a conserved binding epitope inherent to the common fold of the DD superfamily exists (118). Structural comparison of these three pairs of interactions by superimposing DED1 with any of the four proteins in the Pelle DD:Tube DD complex and in the Apaf-1 CARD:caspase-9 CARD complex shows that they all represent different modes of interac- tion. When DED1 is superimposed with ei- ther Pelle DD or TubeDD, the partner of the complex falls onto a different place relative to DED2 (Figures 7a,b). The same is observed when DED1 is superimposed with caspase-9 CARD (Figure 7c). This means that different surfaces are used in each of these complexes. The closest structural similarity is seen when Figure 7 DED1 is superimposed with Apaf-1 CARD Comparison of the three pairs of known interactions in the DD (Figure 7d ) or when DED2 is superimposed superfamily: the Pelle DD:Tube DD complex, the Apaf-1 CARD:caspase-9 with caspase-9 CARD. For both DED2 and CARD complex, and the DED1:DED2 in the tandem DED MC159. caspase-9 CARD, the H1 and H4 helices me- DED1 of MC159 is superimposed with Pelle DD in complex a, Tube DD diate the interaction with the partner. For in complex b, caspase-9 CARD in complex c, and Apaf-1 CARD in complex DED1, the corresponding surface is formed d, respectively. Figure modified from Yang et al. (116). by H2 and H5 helices. For Apaf-1 CARD, the H2 and H3 helices form the surface, which is similar but not identical with the surface used bers of the same subfamily. Currently, we only on DED1. These observations suggest that know two cases of potential heterotypic inter- interactions in the DD superfamily may oc- actions, and it is not known whether these in- cur in different modes. However, there may be teractions are just a few rare examples or rep- 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. certain hot spots for interaction on the surface resent a major functional aspect of the DD of the DD fold. More structures are required superfamily. to further elucidate this. One case of heterotypic interaction is present in the PEA-15 (phosphoprotein enriched in astrocytes 15) DED protein. NONHOMOTYPIC PEA-15 is unusual because it may interact ho- INTERACTIONS motypically with DED-containing proteins Given the high structural similarity among the such as FADD and caspase-8 and heterotyp- subfamilies of the DD superfamily, it is in- ically with non-DED proteins such as the teresting and perhaps surprising that almost MAP kinase ERK (118). Another case of het- all known interactions in the DD superfam- erotypic interaction is present in the CARD- ily are homotypic interactions between mem- containing protein ARC, which appears to

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interact heterotypically with both the DDs of EVOLUTIONARY REMARKS Fas and FADD, and the C terminus of the The DD superfamily is found in many multi- Bcl-2 family protein Bax (BCL2-associated cellular organisms and is evolutionarily con- X protein) (141). These interactions under- served. However, fewer members are present lie ARC’s ability to inhibit both the death in lower organisms such as C. elegans and receptor and the mitochondria cell death Drosophila than in mammals. This expansion pathway. of DD superfamily members is consistent with the expansion of apoptotic and inflam- matory signaling apparatus in mammals and may reflect the much higher complexity of the a Sequence-based phylogenetic tree mammalian signaling system in general. Given the similar fold of the DD super- Fas DD FADD DD family, we were curious about the potential TNFR1 DD evolutionary relationship among these sub- RAIDD DD families and whether the different subfamilies Tube DD arose from a common ancestor. To investi- p75 DD gate this question, we constructed phyloge- IRAK4 DD netic trees among members of the DD su- Pelle DD PEA-15 DED perfamily using either sequence or structural FADD DED similarity (Figure 8). Strikingly, members of MC159 DED1 each subfamily are clustered together without MC159 DED2 a single anomaly, and we predicted a similar ASC PYD evolutionary relationship based both on se- NALP1 PYD quence and structure. This suggests that se- Apaf-1 CARD ICEBERG CARD quence and structural signatures are clearly RAIDD CARD both present to distinguish the subfamilies. Caspase-9 CARD Interestingly, both phylogenetic trees CED-4 CARD placed PYDs and DEDs as more related to each other than to other subfamilies of the b Structure-based phylogenetic tree DD superfamily. One small difference exists RAIDD CARD between the sequence-based and structure- Caspase-9 CARD based phylogenetic trees. The sequence- CED-4 CARD based phylogenetic tree assigned two large Apaf-1 CARD ICEBERG CARD ←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− ASC PYD 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. NALP1 PYD Figure 8 MC159 DED1 Sequence and structural comparisons. (a) FADD DED Phylogenetic tree of the DD superfamily MC159 DED2 constructed on the basis of sequence similarity. PEA-15 DED Only those members with known structures are IRAK4 DD used. The calculation was performed using the Pelle DD multiple sequence alignment program MAFFT Tube DD (http://align.bmr.kyushu-u.ac.jp/mafft/online/ TNFR1 DD server/). (b) Phylogenetic tree of the DD RAIDD DD superfamily constructed based on structural FADD DD similarity. The calculation was performed using the program TraceSuite II (http://www- p75 DD cryst.bioc.cam.ac.uk/∼tracesuite/evoltrace/ Fas DD evoltrace.html).

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branches consisting of DDs in one and teins. In this regard, it is amazing that almost CARDs, DEDs, and PYDs in the other. all oligomeric signaling complexes in apopto- The structure-based tree assigned three equal sis and inflammation contain domains of the branches: the DDs in one, the CARDs in DD superfamily. Through self-associations another, and the DEDs and the PYDs in and homotypic interactions with other mem- the last. bers of each of the subfamilies, these proteins The clear distinction between the subfam- often form the platform of these oligomeric ilies of the DD superfamily may be the under- assemblies to allow proximity-induced cas- lying reason that these proteins almost always pase and kinase activation. interact homotypically with other members of Researchers have performed many bio- the same subfamily. One possible evolution- chemical and structural studies on these ary scenario may be as the following. A pri- domains. These studies have revealed a con- mordial DD superfamily member may have served six-helical bundle fold of the DD su- arisen, and this member may or may not have perfamily. Almost all known protein-protein self-associated. Then an interaction pair may interactions in the superfamily are either self- have arisen between two duplicated modules. association or homotypic interactions with This interaction pair then further duplicated other members of the same subfamily. This is and coevolved into the different subfamilies of somewhat surprising given the structural sim- the DD superfamily. As such the homotypic ilarity among the different subfamilies, but it nature of the interactions is preserved because may reflect evolutionary circumstances. the evolution takes place on the interaction Currently there are only three known pair. structures of homotypic complexes in the en- tire DD superfamily. Interestingly, they are all asymmetric, in contrast to what we might SUMMARY AND FUTURE expect for homotypic interactions. They all PERSPECTIVES also differ in the surfaces used for the inter- The DD superfamily is one of the largest and actions. Given the paucity of structural infor- most widely distributed domain superfamilies. mation on these complexes, the question re- One important function of these domains is to mains whether common modes of interactions participate in homotypic protein-protein in- may be observed from either within the sub- teractions in the assembly of the oligomeric family or within the entire DD superfamily. signaling complexes of apoptosis and inflam- More biochemical and structural studies are mation. Evolutionarily, the ever-expanding required to address this question and to under- DD superfamily may have evolved by insert- stand the molecular basis of these interactions ing into various proteins in the assembly of apoptotic and inflammatory such as caspases, kinases, and adapter pro- signaling complexes. 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.

ACKNOWLEDGMENTS We thank Upendra Maddineni for careful readings of the manuscript. This work was supported by the National Institutes of Health (AI45937 and AI50872). Y.C.L and S.C.L. are postdoc- toral fellows of the Cancer Research Institute. We apologize to all whose work has not been appropriately reviewed or cited owing to space limitations.

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Annual Review of Immunology Contents Volume 25, 2007

Frontispiece Peter C. Doherty pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppx Challenged by Complexity: My Twentieth Century in Immunology Peter C. Doherty ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1 The Impact of Glycosylation on the Biological Function and Structure of Human Immunoglobulins James N. Arnold, Mark R. Wormald, Robert B. Sim, Pauline M. Rudd, and Raymond A. Dwek pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp21 The Multiple Roles of Osteoclasts in Host Defense: Bone Remodeling and Hematopoietic Stem Cell Mobilization Orit Kollet, Ayelet Dar, and Tsvee Lapidot ppppppppppppppppppppppppppppppppppppppppppppppp51 Flying Under the Radar: The Immunobiology of Hepatitis C Lynn B. Dustin and Charles M. Rice ppppppppppppppppppppppppppppppppppppppppppppppppppppp71 Resolution Phase of Inflammation: Novel Endogenous Anti-Inflammatory and Proresolving Lipid Mediators and Pathways Charles N. Serhan pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp101 Immunobiology of Allogeneic Hematopoietic Stem Cell Transplantation Lisbeth A. Welniak, Bruce R. Blazar, and William J. Murphy ppppppppppppppppppppppp139 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. Effector and Memory CTL Differentiation Matthew A. Williams and Michael J. Bevan ppppppppppppppppppppppppppppppppppppppppppp171 TSLP: An Epithelial Cell Cytokine that Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation Yong-Jun Liu, Vasilli Soumelis, Norihiko Watanabe, Tomoki Ito, Yui-Hsi Wang, Rene de Waal Malefyt, Miyuki Omori, Baohua Zhou, and Steven F. Ziegler ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp193 Discovery and Biology of IL-23 and IL-27: Related but Functionally Distinct Regulators of Inflammation Robert A. Kastelein, Christopher A. Hunter, and Daniel J. Cua pppppppppppppppppppppp221

v AR306-FM ARI 13 February 2007 11:22

Improving T Cell Therapy for Cancer Ann M. Leen, Cliona M. Rooney, and Aaron E. Foster pppppppppppppppppppppppppppppppp243 Immunosuppressive Strategies that are Mediated by Tumor Cells Gabriel A. Rabinovich, Dmitry Gabrilovich, and Eduardo M. Sotomayor pppppppppppp267 The Biology of NKT Cells Albert Bendelac, Paul B. Savage, and Luc Teyton pppppppppppppppppppppppppppppppppppppp297 Regulation of Cellular and Humoral Immune Responses by the SLAM and SAP Families of Molecules Cindy S. Ma, Kim E. Nichols, and Stuart G. Tangye pppppppppppppppppppppppppppppppppp337 Mucosal Dendritic Cells Akiko Iwasaki ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp381 Immunologically Active Autoantigens: The Role of Toll-Like Receptors in the Development of Chronic Inflammatory Disease Ann Marshak-Rothstein and Ian R. Rifkin ppppppppppppppppppppppppppppppppppppppppppppp419 The Immunobiology of SARS Jun Chen and Kanta Subbarao pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp443 Nonreceptor Protein-Tyrosine Phosphatases in Immune Cell Signaling Lily I. Pao, Karen Badour, Katherine A. Siminovitch, and Benjamin G. Neel ppppppp473 Fc Receptor-Like Molecules Randall S. Davis pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp525 The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation Hyun Ho Park, Yu-Chih Lo, Su-Chang Lin, Liwei Wang, Jin Kuk Yang, and Hao Wu pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp561 Cellular Responses to Viral Infection in Humans: Lessons from Epstein-Barr Virus Andrew D. Hislop, Graham S. Taylor, Delphine Sauce, and Alan B. Rickinson pppppp587 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. Structural Basis of Integrin Regulation and Signaling Bing-Hao Luo, Christopher V. Carman, and Timothy A. Springer ppppppppppppppppppp619 Zoned Out: Functional Mapping of Stromal Signaling Microenvironments in the Thymus Howard T. Petrie and Juan Carlos Z´u˜niga-Pfl¨ucker ppppppppppppppppppppppppppppppppppp649 T Cells as a Self-Referential, Sensory Organ Mark M. Davis, Michelle Krogsgaard, Morgan Huse, Johannes Huppa, Bjoern F. Lillemeier, and Qi-jing Li ppppppppppppppppppppppppppppppppppppppppppppppppppp681 The Host Defense of Bruno Lemaitre and Jules Hoffmann ppppppppppppppppppppppppppppppppppppppppppppppppppp697

vi Contents AR306-FM ARI 13 February 2007 11:22

Ontogeny of the Hematopoietic System Ana Cumano and Isabelle Godin pppppppppppppppppppppppppppppppppppppppppppppppppppppppp745 Chemokine:Receptor Structure, Interactions, and Antagonism Samantha J. Allen, Susan E. Crown, and Tracy M. Handel pppppppppppppppppppppppppp787 IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages Casey T. Weaver, Robin D. Hatton, Paul R. Mangan, and Laurie E. Harrington ppp821

Indexes

Cumulative Index of Contributing Authors, Volumes 15–25 pppppppppppppppppppppppp853 Cumulative Index of Chapter Titles, Volumes 15–25 ppppppppppppppppppppppppppppppppp860

Errata

An online log of corrections to Annual Review of Immunology chapters (if any, 1997 to the present) may be found at http://immunol.annualreviews.org/errata.shtml 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.

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