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

Kate E. Lawlor (), Nufail Khan, Alison Mildenhall, Motti Gerlic, Ben A. Croker, Akshay A. D’Cruz, Cathrine Hall, Sukhdeep Kaur 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 and James E. Vince ()
Additional contact information
Kate E. Lawlor: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Nufail Khan: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Alison Mildenhall: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Motti Gerlic: Sackler Faculty of Medicine, Tel Aviv University
Ben A. Croker: Boston Children’s Hospital, Harvard Medical School
Akshay A. D’Cruz: Boston Children’s Hospital, Harvard Medical School
Cathrine Hall: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Sukhdeep Kaur Spall: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Holly Anderton: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Seth L. Masters: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Maryam Rashidi: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Ian P. Wicks: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Warren S. Alexander: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
Yasuhiro Mitsuuchi: TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike
Christopher A. Benetatos: TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike
Stephen M. Condon: TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike
W. Wei-Lynn Wong: Institute of Experimental Immunology, University of Zürich
John Silke: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
David L. Vaux: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
James E. Vince: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia

Nature Communications, 2015, vol. 6, issue 1, 1-19

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7282

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