Lawlor, Kate E.Khan, NufailMildenhall, AlisonGerlic, MottiCroker, BenD’Cruz, Akshay A.Hall, CathrineKaur Spall, SukhdeepAnderton, HollyMasters, Seth L.Rashidi, MaryamWicks, Ian P.Alexander, Warren S.Mitsuuchi, YasuhiroBenetatos, Christopher A.Condon, Stephen M.Wong, W. Wei-LynnSilke, JohnVaux, David L.Vince, James E.2015-04-012015Lawlor, K. E., N. Khan, A. Mildenhall, M. Gerlic, B. A. Croker, A. A. D’Cruz, C. Hall, et al. 2015. “RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.” Nature Communications 6 (1): 6282. doi:10.1038/ncomms7282. http://dx.doi.org/10.1038/ncomms7282.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351363RIPK3 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-1β inflammatory responses independent of MLKL and necroptotic cell death.en-USJournal Article2015-04-0110.1038/ncomms7282