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Nat Commun. 2015 Feb 18;6:6282. doi: 10.1038/ncomms7282.

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

Author information

1
1] Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, the University of Melbourne, Parkville, Victoria 3050, Australia.
2
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
3
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike, Malvern, Pennsylvania 19355, USA.
5
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.

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.

PMID:
25693118
PMCID:
PMC4346630
DOI:
10.1038/ncomms7282
[Indexed for MEDLINE]
Free PMC Article

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