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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.

Original publication

DOI

10.1038/ncomms7282

Type

Journal article

Journal

Nat Commun

Publication Date

18/02/2015

Volume

6

Keywords

Animals, Apoptosis, Autoantibodies, Bone Marrow Cells, Carrier Proteins, Caspase 8, Enzyme Activation, Female, Inflammasomes, Inflammation, Inhibitor of Apoptosis Proteins, Interleukin-1beta, Lipopolysaccharides, Liver, Male, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Necrosis, Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Tumor Necrosis Factor-alpha, X-Linked Inhibitor of Apoptosis Protein