2013
DOI: 10.1101/gad.223321.113
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RIP3: a molecular switch for necrosis and inflammation

Abstract: The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3… Show more

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Cited by 298 publications
(275 citation statements)
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References 98 publications
(116 reference 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%
“…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%
“…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.…”
mentioning
confidence: 99%
“…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.…”
mentioning
confidence: 99%