The Structure of FADD and Its Mode of Interaction with Procaspase-8

Carrington, Paul E.; Sandu, Cristinel; Wei, Yufeng; Hill, Jennifer; Morisawa, Gaku; Huang, Ted; Gavathiotis, Evripidis; Wei, Yu; Werner, M.D.

doi:10.1016/j.molcel.2006.04.018

Cited by 162 publications

(178 citation statements)

References 51 publications

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“…In the case of TNFa-or FasL-induced apoptosis, complex II or DISC drives dimerization and activation of monomeric caspase-8 via FADD [13,14]. Since on one hand HSV-2 R1 interacts with the DEDs of caspase-8 and on the other hand FADD contains a DED involved in both FADD self-association and caspase-8 interaction [67], we investigated putative interaction between FADD and HSV-2 R1. We have been unable to detect, by co-immunoprecipitation, any interaction between HSV-2 R1 and endogenous or over-expressed FADD, indicating that the interaction is specific to the tandem DEDs contained in the caspase-8 prodomain.…”

Section: Discussionmentioning

confidence: 99%

“…We have been unable to detect, by co-immunoprecipitation, any interaction between HSV-2 R1 and endogenous or over-expressed FADD, indicating that the interaction is specific to the tandem DEDs contained in the caspase-8 prodomain. A recent report identified the caspase-8-specific binding surface on FADD and suggested preferential interaction of caspase-8 DED-B with FADD DED [67]. Since HSV-2 R1 interacts with the caspase-8 prodomain, it is conceivable that oligomerized HSV-2 R1 could sterically hinder the site of caspase-8 interaction with FADD DED.…”

Section: Discussionmentioning

confidence: 99%

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The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

et al. 2010

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We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha-(TNFa) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellularregulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-jB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein-Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6D showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.Keywords FasL Á ICP6 Á ICP10 Á Viral inhibitor of apoptosis Á Caspase-8Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

et al. 2010

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“…Pro-caspase-8 is recruited to DISC by FADD, and dimerization or trimerization triggers pro-caspase-8 activation via reciprocal cleavage. Caspase-8, in turn, cleaves and activates caspase-3, -7, Bid, and also NF-kB [52,53]. Caspase-8 activation is regulated by cFLIP that is structurally homologous to caspase-8 but does not have caspase activity [54].…”

Section: Caspase Family Membersmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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“…13,14 Similar to FADD, each DED of MC159 contains two prominent surface features important for protein interactions that distinguish them from other death motifs, namely a hydrophobic patch and a charge triad, also known as RxDL motif. [13][14][15][16] Although the structure of MC159 provides a template for understanding the mechanism of FLIP inhibition, it is unknown which structural motifs mediate DISC recruitment of cellular FLIP proteins. In the present study, we characterize for the first time the short isoform of murine c-FLIP and show that c-FLIP R but not c-FLIP short is the sole truncated isoform expressed in murine cells.…”

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confidence: 99%

Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment

et al. 2008

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Cellular FLICE-inhibitory protein (c-FLIP) proteins are known as potent inhibitors of death receptor-mediated apoptosis by interfering with caspase-8 activation at the death-inducing signaling complex (DISC). Among the three human isoforms, c-FLIP long , c-FLIP short and c-FLIP R , the latter isoform is poorly characterized. We report here the characterization of murine c-FLIP R and show that it is the only short c-FLIP isoform expressed in mice. By generating several mutants, we demonstrate that both death effector domains (DEDs) are required for DISC binding and the antiapoptotic function of c-FLIP R . Surprisingly, the C-terminal tail is important for both protein stability and DISC recruitment. Three-dimensional modeling of c-FLIP R revealed a substantial similarity of the overall structures and potential interaction motifs with the viral FLIP MC159. We found, however, that c-FLIP R uses different structural motifs for its DISC recruitment. Whereas MC159 interferes with interaction and selfoligomerization of the DISC component FADD by its extensive hydrophilic surface, a narrow hydrophobic patch of c-FLIP R on the surface of DED2 is crucial for DISC association. Thus, despite the presence of similar tandem DEDs, viral and cellular FLIPs inhibit apoptosis by remarkably divergent mechanisms. Death receptors like CD95 (Fas/Apo-1) transduce death signals upon ligand binding and formation of a death-inducing signaling complex (DISC), which comprises the receptor, the adaptor protein Fas-associated death domain (FADD) and procaspase-8 (FLICE) or procaspase-10. 1 This assembly brings procaspase-8/10 in close proximity to the receptor and allows them to be activated by dimerization. 2-4 Activation of the initiator caspases can be counteracted by FLICEinhibitory proteins (FLIPs). 5,6 Next to viral FLIP (v-FLIP) proteins, 7 three cellular homologs (cellular FLICE-inhibitory proteins (c-FLIPs)) have been identified, namely c-FLIP long , c-FLIP short and c-FLIP R , which are generated by differential splicing. [8][9][10] The C-terminus of c-FLIP long contains a catalytically inactive caspase-like domain, whereas c-FLIP short and c-FLIP R have only a truncated C-terminus.As a characteristic feature, FLIP proteins contain tandem death effector domains (DEDs), which mediate their recruitment into the DISC. 10,11 The DED forms a bundle of six antiparallel a-helices similar to the death domain (DD) and the caspase recruitment domain (CARD), two other signaling motifs involved in homotypic protein interactions. 12 Curiously, despite their importance in apoptosis, there are currently no reported structures for cellular FLIP proteins. Only the structure of the tandem DEDs of the v-FLIP MC159 from Molluscum contagiosum has been reported showing a rigidly associated dumbbell-shaped molecule, which is tightly packed by an extensive hydrophobic interface between its two DEDs. 13,14 Similar to FADD, each DED of MC159 contains two prominent surface features important for protein interactions that distinguish them from other death mot...

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The Structure of FADD and Its Mode of Interaction with Procaspase-8

Cited by 162 publications

References 51 publications

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

Major apoptotic mechanisms and genes involved in apoptosis

Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment

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