Caspase 8 inhibits programmed necrosis by processing CYLD

O’Donnell, Marie Anne; Pérez-Jiménez, Eva; Oberst, Andrew; Ng, Aylwin; Massoumi, Ramin; Xavier, Ramnik J.; Green, Douglas R.; Ting, Adrian T.

doi:10.1038/ncb2362

Cited by 428 publications

(403 citation statements)

References 33 publications

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“…From the cells co-expressing FKBP-RIP1 RHIM mut , FRB*-RIP3 WT , and HA-RIP3, we found that HA-RIP3 only interacted with AP21976-induced RIP1 RHIM mut -RIP3 WT complex, but not RIP1 RHIM mut -RIP3 RHIM mut complex (Figure 2g), thereby suggesting that inducible RIP1-RIP3 heterodimer could recruit another RIP3 protein and this recruitment may be required for necroptosis. Caspase-8 is known to inhibit necroptosis 19,20,31 and zVAD indeed tended to increase the cell death induced by RIP1-RIP3 complex, although the enhancement is not always statistically significant (Figures 2c, d and f). The participation of caspase-8 in RIP1-RIP3 dimer-induced cell death was supported by the data that caspase-8 can be detected in AP21967-induced RIP1-RIP3 complex (Supplementary Figure S2d).…”

Section: Resultsmentioning

confidence: 95%

“…25,26 Caspase-8 and FADD negatively regulates necroptosis, [27][28][29][30] because RIP1, RIP3, and CYLD are potential substrates of caspase-8. [31][32][33][34] Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (MLKL) is downstream of RIP3, 35,36 and phosphorylation of MLKL is required for necroptosis.…”

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confidence: 99%

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Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

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Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis. Cell Death and Differentiation (2014) 21, 1709-1720; doi:10.1038/cdd.2014.77; published online 6 June 2014Necroptosis is a type of programmed necrosis characterized by necrotic morphological changes, including cellular organelle swelling, cell membrane rupture, 1-3 and dependence of receptor-interacting protein (RIP)1 4 and RIP3. [5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, 12-16 tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis. If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD, [22][23][24] caspase-8, RIP1, and RIP3, and the cells undergo necroptosis. 25,26 Caspase-8 and FADD negatively regulates necroptosis, 27-30 because RIP1, RIP3, and CYLD are potential substrates of caspase-8. [31][32][33][34] Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (ML...

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

et al. 2014

Cell Death Differ

258

230

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“…Deubiquitination of RIPK1 is known to be the critical process for assembly of the necroptotic complex. 62,76 Conversely, stabilization of RIPK1 polyubiquitin chain prevents necroptosis. 76 As discussed earlier, TAB2 is a polyubiquitin chain-binding protein and directly binds to TAK1.…”

Section: Tak1 As a Necroptosis Inducermentioning

confidence: 99%

TAK1 control of cell death

2014

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Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-b-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra-and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-jB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-jB but also through NF-jB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.

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“…66 Caspase 8 has also been shown to repress necrosis by processing CYLD. 67 Interestingly, caspase 8 appears to act in a proteolytically active complex with FADD and cFLIP to block RIP1-and RIP3-mediated necrosis, 65,68 with c-FLIP- 69 and FADD-70,71 deficient cells being highly sensitive to death by necrosis. This is consistent with the developmental lethality, due to cardiac failure, in FADDdeficient embryos, 72 with RIP1 deficiency rescuing the embryonic lethality associated with FADD deficiency.…”

Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning

confidence: 99%