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

Fu, Tao; Li, Yang; Lu, Alvin; Li, Zongli; Vajjhala, Parimala R.; Cruz, Anthony; Srivastava, Divya; DiMaio, Frank; Penczek, Pawel A.; Siegel, Richard M.; Stacey, Katryn J.; Egelman, Edward H.; Wu, Hao

doi:10.1016/j.molcel.2016.09.009

Cited by 141 publications

(232 citation statements)

References 47 publications

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“…Procaspase-8 binds to the exposed DED of death receptor-associated FADD through a pocket in its DED1, forming the DISC (19, 20) (Figure 1). Additional procaspase-8 molecules are then recruited and bind through a second DED1 pocket to a motif in DED2 of the prior procaspase-8 by dominant hydrophobic interactions (20).…”

Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

“…Additional procaspase-8 molecules are then recruited and bind through a second DED1 pocket to a motif in DED2 of the prior procaspase-8 by dominant hydrophobic interactions (20). This results in DED-mediated procaspase-8 oligomerization.…”

Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

“…This results in DED-mediated procaspase-8 oligomerization. Binding of procaspase-8 to FADD thus prompts recruitment of additional procaspase-8 molecules that leads to the formation of a filament assembled in a unidirectional manner (20). Stoichiometric studies show that on average six procaspase-8 molecules bind to a single FADD protein (19).…”

Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

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Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

552

421

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Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

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Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

Section: Caspase-8 In Executing Extrinsic Apoptosismentioning

confidence: 99%

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Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

552

421

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“…All the current models propose that chains containing procaspase‐8 and FLIP are formed following DISC stimulation; it is the length of these chains and whether they require just a single ‘nucleating’ FADD DED or bridging interactions between FADD DEDs bound to adjacent receptors that remain unresolved. An interesting further development is the proposal that parallel DED chains can intertwine to generate ‘DED filaments’ . Downstream of caspase‐8 activation, apoptosis can be induced directly by activation of executioner caspases‐3/7 (in so‐called Type‐I cells) or more usually by amplification via the intrinsic mitochondrial‐mediated apoptotic pathway (in Type‐II cells) by cleavage of the Bcl‐2 family member Bid which can promote mitochondrial outer membrane permeabilization (MOMP) by interacting with other members of the Bcl‐2 family, Bax and Bak (Fig.…”

Section: Canonical Flip Biology: Regulation Of Caspase‐8 Activationmentioning

confidence: 99%

FLIP as a therapeutic target in cancer

2018

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One of the classic hallmarks of cancer is disruption of cell death signalling. Inhibition of cell death promotes tumour growth and metastasis, causes resistance to chemo‐ and radiotherapies as well as targeted agents, and is frequently due to overexpression of antiapoptotic proteins rather than loss of pro‐apoptotic effectors. FLIP is a major apoptosis‐regulatory protein frequently overexpressed in solid and haematological cancers, in which its high expression is often correlated with poor prognosis. FLIP, which is expressed as long (FLIP(L)) and short (FLIP(S)) splice forms, achieves its cell death regulatory functions by binding to FADD, a critical adaptor protein which links FLIP to the apical caspase in the extrinsic apoptotic pathway, caspase‐8, in a number of cell death regulating complexes, such as the death‐inducing signalling complexes (DISCs) formed by death receptors. FLIP also plays a key role (together with caspase‐8) in regulating another form of cell death termed programmed necrosis or ‘necroptosis’, as well as in other key cellular processes that impact cell survival, including autophagy. In addition, FLIP impacts activation of the intrinsic mitochondrial‐mediated apoptotic pathway by regulating caspase‐8‐mediated activation of the pro‐apoptotic Bcl‐2 family member Bid. It has been demonstrated that FLIP can not only inhibit death receptor‐mediated apoptosis, but also cell death induced by a range of clinically relevant chemotherapeutic and targeted agents as well as ionizing radiation. More recently, key roles for FLIP in promoting the survival of immunosuppressive tumour‐promoting immune cells have been discovered. Thus, FLIP is of significant interest as an anticancer therapeutic target. In this article, we review FLIP's biology and potential ways of targeting this important tumour and immune cell death regulator.

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“…ASC specks also recruit caspase‐8, which is activated in the absence of caspase‐1 and GSDMD, thus representing a backup mechanism to trigger apoptosis in case pyroptosis is impaired . While it is clear that ASC can nucleate caspase‐8 filaments in vitro, it is not known how the selective autocatalytic activation of caspase‐8 in case of abrogated pyroptosis is achieved on the molecular level. It is conceivable that pro‐caspase‐1 and pro‐caspase‐8 compete for ASC CARD ‐binding sites in the speck, form mixed polymers of caspase‐1 CARD and caspase‐8 tDED , influence each other's activation, or are subject to different regulatory factors.…”

Section: Function Of Asc Specksmentioning

confidence: 99%

The intra‐ and extracellular functions of ASC specks

Franklin

Latz

Schmidt

2017

Immunological Reviews

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Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation.

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

Cited by 141 publications

References 47 publications

Caspase‐8: regulating life and death

Caspase‐8: regulating life and death

FLIP as a therapeutic target in cancer

The intra‐ and extracellular functions of ASC specks

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