Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL

Kaiser, William J.; Sridharan, Haripriya; Huang, Chunzi; Mandal, Pratyusha; Upton, Jason W.; Gough, Peter J.; Sehon, Clark A.; Marquis, Robert W.; Bertin, John; Mocarski, Edward S.

doi:10.1074/jbc.m113.462341

Cited by 806 publications

(868 citation statements)

References 60 publications

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“…102,103 However, under circumstances of FADD depletion or its phosphorylation on serine residue 191 (during cell cycle arrest) or when caspases are inactivated (as occurs in virus-infected cells), IFNs can feed back on virally infected cells to activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 and triggers RIP1/RIP3-mediated necroptosis. 107 When caspases are inhibited, TLR3 and TLR4 can also directly induce necroptosis by virtue of the RHIM motif of TRIF engaging RIP3 and MLKL to trigger downstream necrosis 108,109 (Figure 3). Interestingly, whereas RIP1 is required to mediate TNF-induced RIP3-dependent This leads to ubiquitination of TRAF6, TAK1/IKK-mediated activation of NFkB and induction of pro-inflammatory genes such as IL-1b and TNF.…”

Section: Rip Kinases and Tlrsmentioning

confidence: 99%

“…79 TLRs that do not employ TRIF can also induce necroptosis in an indirect manner by inducing TNF to trigger necrosis via TNFR-1 as described above. 109 In addition, some of these pathways have been associated with cell apoptosis. Overexpression of TRIF results in interaction with RIP1 and RIP3 and induction of apoptosis, 110 and in the context of TLR3 signalling in lung cancer cells, the TLR3 ligand dsRNA can induce apoptosis by recruiting caspase 8 to TLR3 in a RIP1-dependent manner.…”

Section: Rip Kinases and Tlrsmentioning

confidence: 99%

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RIP kinases: key decision makers in cell death and innate immunity

et al. 2014

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Section: Rip Kinases and Tlrsmentioning

confidence: 99%

Section: Rip Kinases and Tlrsmentioning

confidence: 99%

RIP kinases: key decision makers in cell death and innate immunity

et al. 2014

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“…Mixed-lineage kinase domain-like (MLKL) is downstream of RIP3, 35,36 and phosphorylation of MLKL is required for necroptosis. [37][38][39][40][41][42] Apoptosis inducing complex (complex II) and necrosome are both supramolecular complexes. [43][44][45] A recent study showed that RIP1 and RIP3 form amyloidal fibrils through their RIP homotypic interaction motif 46 (RHIM)-mediated polymerization, and suggested that amyloidal structure is essential for necroptosis signaling.…”

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confidence: 99%

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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“…We also analysed primary MDFs and keratinocytes, isolated from mutant and knockout mouse strains that were deficient for cell death ligands and receptors. Fasl gld/gld Tnf -− / − and Ifnar − / − MDFs, and 29,38 We therefore generated MDFs lacking DAI, TRIF and PKR, which are known to be upregulated by interferons 39 and implicated in cell death. 29 Figure S3D).…”

Section: Resultsmentioning

confidence: 99%

Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways

et al. 2017

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Peptido-mimetic inhibitor of apoptosis protein (IAP) antagonists (Smac mimetics (SMs)) can kill tumour cells by depleting endogenous IAPs and thereby inducing tumour necrosis factor (TNF) production. We found that interferon-γ (IFNγ) synergises with SMs to kill cancer cells independently of TNF − and other cell death receptor signalling pathways. Surprisingly, CRISPR/Cas9 HT29 cells doubly deficient for caspase-8 and the necroptotic pathway mediators RIPK3 or MLKL were still sensitive to IFNγ/SMinduced killing. Triple CRISPR/Cas9-knockout HT29 cells lacking caspase-10 in addition to caspase-8 and RIPK3 or MLKL were resistant to IFNγ/SM killing. Caspase-8 and RIPK1 deficiency was, however, sufficient to protect cells from IFNγ/SM-induced cell death, implying a role for RIPK1 in the activation of caspase-10. These data show that RIPK1 and caspase-10 mediate cell death in HT29 cells when caspase-8-mediated apoptosis and necroptosis are blocked and help to clarify how SMs operate as chemotherapeutic agents.

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Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL

Cited by 806 publications

References 60 publications

RIP kinases: key decision makers in cell death and innate immunity

RIP kinases: key decision makers in cell death and innate immunity

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

Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways

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