RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
- Author(s)
- Lawlor, KE; Khan, N; Mildenhall, A; Gerlic, M; Croker, BA; D'Cruz, AA; Hall, C; Kaur Spall, S; Anderton, H; Masters, SL; Rashidi, M; Wicks, IP; Alexander, WS; Mitsuuchi, Y; Benetatos, CA; Condon, SM; Wong, WW; Silke, J; Vaux, DL; Vince, JE;
- Journal Title
- Nat Commun
- Publication Type
- Journal Article
- Abstract
- RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1beta inflammatory responses independent of MLKL and necroptotic cell death.
- Publisher
- NPG
- Research Division(s)
- Inflammation
- Publisher's Version
- https://doi.org/10.1038/ncomms7282
- Open Access at Publisher's Site
http://www.nature.com/ncomms/2015/150218/ncomms7282/full/ncomms7282.html- NHMRC Grants
- NHMRC/1051210, NHMRC/1025594, NHMRC/1057905, NHMRC/1052598, NHMRC/1023407, NHMRC/541901,
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- Refer to copyright notice on published article.
Creation Date: 2015-02-20 02:15:09
Last Modified: 2015-05-12 09:40:29