RIP3: a molecular switch for necrosis and inflammation

Moriwaki, Kazuo; Chan, Francis Ka‐Ming

doi:10.1101/gad.223321.113

Cited by 311 publications

(284 citation statements)

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“…This is surprising, because TNFinduced necroptosis is frequently considered to be more pro-inflammatory than TNF-initiated outcomes that occur in the presence of caspase activity. 22,[27][28][29] This view appears to be predicated upon the notion that TNF promotes either apoptosis or necrosis, with the latter typically being proinflammatory and the former not. However, because TNF is itself highly pro-inflammatory as illustrated above (Figures 1a and b), the impact of necroptosis on TNF-induced inflammatory events remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

et al. 2015

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Section: Resultsmentioning

confidence: 99%

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

et al. 2015

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“…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.…”

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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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“…Despite some reports to this effect, 8,9,22 RIPK3 has been described as the necroptotic 'switch', implying its activity precipitates necroptosis to the exclusion of apoptosis. [23][24][25] Here, we have directly activated RIP kinases without the confounding effects of multiple signals emanating from the target cell's cytokine receptors, allowing us to define more precisely the functions of RIPK1 and RIPK3. We activated RIP kinases by dimerization using inducible lentiviral vectors, each encoding a chimera of a RIP kinase with subunit B of E. coli DNA gyrase.…”

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RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

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RIP3: a molecular switch for necrosis and inflammation

Cited by 311 publications

References 98 publications

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

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

RIPK1- and RIPK3-induced cell death mode is determined by target availability

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