RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL Academic Article uri icon


  • 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.


  • 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, WWL
  • Silke, J
  • Vaux, DL
  • Vince, JE

publication date

  • 2015

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