Portal de Periódicos da CAPES

RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms7282

2041-1723

Kate E. Lawlor, Nufail Khan, Alison Mildenhall, Motti Gerlic, Ben A. Croker, Akshay A. D’Cruz, Cathrine Hall, Sukhdeep K. Spall, Holly Anderton, Seth L. Masters, Maryam Rashidi, Ian P. Wicks, Warren S. Alexander, Yasuhiro Mitsuuchi, Christopher A. Benetatos, Stephen M. Condon, W. Wei‐Lynn Wong, John Silke, David L. Vaux, James E. Vince,

Phagocytosis and Immune Regulation

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-1β inflammatory responses independent of MLKL and necroptotic cell death.