Requirement of cooperative functions of two repeated death effector domains in caspase‐8 and in MC159 for induction and inhibition of apoptosis, respectively

Tsukumo, Shin-ichi; Yonehara, Shin

doi:10.1046/j.1365-2443.1999.00280.x

Cited by 28 publications

(14 citation statements)

References 26 publications

(44 reference statements)

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“…The Casp-8 filament structure corrects the DED chain model proposed previously, which exclusively relies on the type I interaction, by illustrating the importance of type II and III interactions in FasL-induced apoptosis and in recruitment to ASC specks. The filamentous model is consistent with previous studies, in which both DED domains of Casp-8 were shown to be required for FADD recruitment and Casp-8 self-association (Siegel et al, 1998; Tsukumo and Yonehara, 1999). Similar to the DED chain model, the filamentous DED interactions explain the unequal and variable stoichiometry among the component proteins in the DISC, in particular with Casp-8 overstoichiometric to FADD (Dickens et al, 2012; Schleich et al, 2012).…”

Section: Discussionsupporting

confidence: 91%

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

et al. 2016

Molecular Cell

138

218

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Summary Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryo-electron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and further confirmed by structure-based mutagenesis in filament formation in vitro, and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8, and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.

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Section: Discussionsupporting

confidence: 91%

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

et al. 2016

Molecular Cell

138

218

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“…Based on prior studies, v-FLIP is thought to prevent apoptosis by binding to FADD and caspase-8 (2,21,25,26). In order to identify functionally important regions of MC159, we constructed a series of mutations in which charged amino acids were changed to alanines.…”

mentioning

confidence: 99%

Binding of FADD and Caspase-8 to Molluscum Contagiosum Virus MC159 v-FLIP Is Not Sufficient for Its Antiapoptotic Function

Garvey¹,

Bertin²,

Siegel

et al. 2002

J Virol

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Molluscum contagiosum virus (MCV), a member of the human poxvirus family, encodes the MC159 protein that inhibits Fas-, tumor necrosis factor (TNF)-, and TNF-related apoptosis-inducing ligant (TRAIL)-induced apoptosis. We used site-directed mutagenesis to change charged or hydrophobic amino acid residues to alanines to identify regions of MC159 that are critical for protection from apoptosis and for protein-protein interactions. Surprisingly, while MC159 is thought to block apoptosis by binding to Fas-associated death domain (FADD) or caspase-8, several mutants that lost apoptosis blocking activity still bound to both FADD and caspase-8. Mutations in the predicted hydrophobic patch 1 and ␣2 regions of both death effector domains (DEDs) within MC159 resulted in loss of the ability to bind to FADD or caspase-8 and to block apoptosis. Amino acid substitutions in the RXDL motif located in the ␣6 region of either DED resulted in loss of protection from apoptosis induced by Fas, TNF, and TRAIL and abolished the ability of MC159 to block death effector filament formation. Thus, charged or hydrophobic amino acids in three regions of the MC159 DEDs (hydrophobic patch 1, ␣2, and ␣6) are critical for the protein's ability to interact with cellular proteins and to block apoptosis.Death receptors constitute a subgroup of the tumor necrosis factor (TNF) receptor superfamily, which are defined by the presence of a signaling domain with six ␣-helices in the cytoplasmic region that is termed the death domain (13). These receptors function to maintain homeostasis in the immune system by eliminating autoreactive cells, antigen-reactive T cells following an immune response, and virus-infected or malignant cells. In humans, six death receptors have been identified: Fas (also called CD95 and APO-1), TNF receptor 1 (TNFR1; also called TNFRSF1A and CD120a p55-R), DR3 (also called APO3, Wsl-1, TRAMP. and LARD), DR4 (also called TRAIL-R1 and Apo-2), DR5 (also called TRAIL-R2, KILLER, and TRICK2), and DR6 (17,19).Binding of a death receptor to its ligand initiates a change in the receptor complex, resulting in signaling through a series of protein-protein interactions that culminate in apoptosis (4, 22). Fas binding to its ligand (FasL) leads to the recruitment of the adapter molecule FADD (Fas-associated death domain) through interactions of the death domains in Fas and FADD. FADD contains another region known as the death effector domain (DED). The FADD DED also possesses six ␣-helices in a folded region similar to the death domains, but it forms distinct contacts only with other DED-containing proteins, whereas death domain-containing proteins interact chiefly with other death domain-containing adapter proteins.Once FADD is recruited to Fas, its DED binds to the DEDs in the prodomain of caspase-8 or caspase-10 (1, 28). The complex containing Fas, FADD, and caspase-8 or caspase-10 is termed the death-inducing signaling complex (DISC). Recruitment of caspase-8 or caspase-10 into the DISC results in autocatalytic cleavage of the caspase i...

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“…However, determination of the complete MCV genome sequence (24,25) and subsequent functional studies revealed several potential immune-evasion mechanisms, some of which had not previously been described for any virus (21). MCV immuneevasion genes include a viral homolog of cellular chemokines with chemokine antagonist activity (9,17,19), a major histocompatibility complex class I homolog that binds ␤2 microglobulin (26), a selenocysteine-containing glutathione peroxidase that inhibits peroxide-and UV-mediated apoptosis (28), a death effector domain protein that inhibits tumor necrosis factor alpha-and Fas ligand-mediated apoptosis (4,14,27,29,33,34), and an interleukin-18 (IL-18)-binding protein that inhibits the gamma interferon (IFN-␥)-inducing activity of IL-18 (39).…”

mentioning

confidence: 99%

Correspondence of the Functional Epitopes of Poxvirus and Human Interleukin-18-Binding Proteins

Xiang

Moss

2001

J Virol

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Molluscum contagiosum virus, a human poxvirus that causes persistent small benign skin tumors, encodes a variety of putative immune defense proteins. Three such proteins, MC51L, MC53L, and MC54L, have 20 to 35% amino acid sequence identities with human interleukin-18 (hIL-18)-binding protein (hIL-18BP), a naturally occurring antagonist of the proinflammatory cytokine IL-18. We previously demonstrated that seven amino acids within the immunoglobulin-like domain of hIL-18BP were important for high-affinity binding to hIL-18. Model building indicated that MC54L, which has been shown to bind hIL-18, contains five of the seven amino acids at corresponding positions in its immunoglobulin-like domain, the exceptions being the conservative substitution of isoleucine for a leucine and the nonconservative substitution of valine for a phenylalanine. We found that individual alanine substitutions for these six identical or highly conserved amino acids of MC54L caused changes in affinity and binding free energy for hIL-18 that were quantitatively similar to those produced by mutagenesis of hIL-18BP. Furthermore, when the nonconserved valine of MC54L was mutated to phenylalanine, making it more like hIL-18BP, its affinity for hIL-18 increased more than 10-fold. In addition, the carboxyl-terminal half of MC54L, which has no similarity with hIL-18BP, was dispensable for hIL-18 binding. Thus, despite their relatively low overall sequence identity, MC54L and hIL-18BP have similar hIL-18 binding sites and functional epitopes. On the other hand, MC51L and MC53L have nonconservative substitutions of three to six of the seven critical amino acids of hIL-18BP and neither protein bound hIL-18, suggesting that they may interact with unidentified ligands.

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Requirement of cooperative functions of two repeated death effector domains in caspase‐8 and in MC159 for induction and inhibition of apoptosis, respectively

Cited by 28 publications

References 26 publications

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

Binding of FADD and Caspase-8 to Molluscum Contagiosum Virus MC159 v-FLIP Is Not Sufficient for Its Antiapoptotic Function

Correspondence of the Functional Epitopes of Poxvirus and Human Interleukin-18-Binding Proteins

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