The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments

Vajjhala, Parimala R.; Lu, Alvin; Brown, Darren L.; Pang, Siew Wai; Sagulenko, Vitaliya; Sester, David P.; Cridland, Simon O.; Hill, Jennifer; Schroder, Kate; Stow, Jennifer L.; Wu, Hao; Stacey, Katryn J.

doi:10.1074/jbc.m115.687731

Cited by 74 publications

(101 citation statements)

References 68 publications

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“…We showed previously that the inflammasome adaptor ASC is able to recruit Casp-8 through a PYD/tDED interaction (Vajjhala et al, 2015). Inflammasome activation or ASC expression leads to formation of a single speck per cell (Hornung et al, 2009) and ASC interaction localizes Casp-8 into these specks.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, DED-mediated interaction between FADD and Casp-8 is the converging downstream element critical for cell death induction (Figure 1A). In addition, recent studies suggested that the inflammasome adaptor ASC recruits Casp-8 through a PYD/tDED interaction to induce apoptosis (Sagulenko et al, 2013; Vajjhala et al, 2015) (Figure 1A). …”

Section: Introductionmentioning

confidence: 94%

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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

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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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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

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201

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“…Barbero et al [32] reported that phosphorylation of Tyr380 in caspase-8 was critical for the promotion of cancer cell migration, and explained that caspase-8 associated with focal adhesion complex, including FAK and Calpain 2, and it promoted tumor cell migration and metastasis [48]. Furthermore, it has been reported that ASC bound to caspase-8 DED through its PYD [33,34]. If ASC binds to caspase-8 in B16BL6 cells, ASC ablation may have made Src more accessible to caspase-8, thus enhancing its phosphorylation and ensuing cellular migration.…”

Section: Discussionmentioning

confidence: 99%

“…Barbero et al [32] uncovered that phosphorylation of Tyr380, which is located in the catalytic domain of caspase-8, was critical for the promotion of cancer cell migration. Accordingly, we examined the effect of a caspase inhibitor, z-VAD-fmk, on cell migration and invadopodia formation since it has also been shown that ASC could interact with caspase-8 [33,34]. We observed that z-VAD-fmk inhibited the cellular motility enhanced by ASC ablation and slightly affected basal cellular migration ability (Fig.…”

Section: Caspase Inhibitors Attenuated the Cellular Motility Of Asc-kmentioning

confidence: 90%

Novel role of ASC as a regulator of metastatic phenotype

Okada

Fujii

Matsumura

et al. 2017

Journal of Dermatological Science

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“…The N-terminal domains of NLRs in both plants and animals are variable and are necessary for signal transduction (Bernoux et al, 2011a;Bai et al, 2012;Proell et al, 2013;Vajjhala et al, 2015). In plant NLRs there are two predominant types: the TIR and CC domains.…”

Section: Nlr Domain Architecture and Domain Functionsmentioning

confidence: 99%

Animal NLRs provide structural insights into plant NLR function

Bentham

Burdett

Anderson

et al. 2016

Ann Bot

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Background The plant immune system employs intracellular NLRs (nucleotide binding [NB], leucine-rich repeat [LRR]/nucleotide-binding oligomerization domain [NOD]-like receptors) to detect effector proteins secreted into the plant cell by potential pathogens. Activated plant NLRs trigger a range of immune responses, collectively known as the hypersensitive response (HR), which culminates in death of the infected cell. Plant NLRs show structural and functional resemblance to animal NLRs involved in inflammatory and innate immune responses. Therefore, knowledge of the activation and regulation of animal NLRs can help us understand the mechanism of action of plant NLRs, and vice versa.Scope This review provides an overview of the innate immune pathways in plants and animals, focusing on the available structural and biochemical information available for both plant and animal NLRs. We highlight the gap in knowledge between the animal and plant systems, in particular the lack of structural information for plant NLRs, with crystal structures only available for the N-terminal domains of plant NLRs and an integrated decoy domain, in contrast to the more complete structures available for animal NLRs. We assess the similarities and differences between plant and animal NLRs, and use the structural information on the animal NLR pair NAIP/NLRC4 to derive a plausible model for plant NLR activation.Conclusions Signalling by cooperative assembly formation (SCAF) appears to operate in most innate immunity pathways, including plant and animal NLRs. Our proposed model of plant NLR activation includes three key steps: (1) initially, the NLR exists in an inactive auto-inhibited state; (2) a combination of binding by activating elicitor and ATP leads to a structural rearrangement of the NLR; and (3) signalling occurs through cooperative assembly of the resistosome. Further studies, structural and biochemical in particular, will be required to provide additional evidence for the different features of this model and shed light on the many existing variations, e.g. helper NLRs and NLRs containing integrated decoys.

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The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments

Cited by 74 publications

References 68 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

Novel role of ASC as a regulator of metastatic phenotype

Animal NLRs provide structural insights into plant NLR function

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