Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium

Robinson, Nirmal; McComb, Scott; Mulligan, Rebecca; Dudani, Renu; Krishnan, Lakshmi; Sad, Subash

doi:10.1038/ni.2397

Cited by 378 publications

(395 citation statements)

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“…38 However, infection of RIPK3 null macrophages (incapable of undergoing necroptosis) led to decreased bacterial burdens, suggesting that rapid RIPK3-dependent necroptosis of macrophages is beneficial to the pathogen and helps to attenuate the host immune response.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…[5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, [12][13][14][15][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).…”

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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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“…1,2,5 Necrosome assembly can be induced via specific death receptors or toll-like receptors, among other modules. [6][7][8][9] The activated necrosome engages MLKL by RIPK3-mediated phosphorylation. 6,10,11 MLKL then oligomerizes and binds to membrane phospholipids, forming pores that cause necroptotic cell death.…”

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confidence: 99%

“…10,[12][13][14][15] Unchecked necroptosis disrupts embryonic development in mice and contributes to several human diseases. 7,8,[16][17][18][19][20][21][22] The apoptotic mediators FADD, caspase-8 and cFLIP suppress necroptosis. [19][20][21]23,24 Elimination of any of these genes in mice causes embryonic lethality, subverted by additional deletion of RIPK3 or MLKL.…”

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confidence: 99%

TRAF2 is a biologically important necroptosis suppressor

et al. 2015

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Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptorinteracting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.

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Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium

Cited by 378 publications

References 50 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

TRAF2 is a biologically important necroptosis suppressor

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