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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.
Highlights
RIPK3 and its substrate mixed lineage kinase domain-like (MLKL) are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules
X-linked IAP (XIAP) loss is required for LPS or tumour-necrosis factor (TNF)-induced IL-1b secretion
inhibitor of apoptosis proteins (IAPs) antagonist compounds are better tolerated in vivo when their functional affinity for XIAP is less than for cIAP1/2 ref
Summary
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Combined loss of XIAP and cIAP1, or cIAP1 and cIAP2, causes embryonic lethality at E10.5 with a similar phenotype, and both doubly deficient IAP embryos are rescued to BE14.5–E16.5 by RIPK1 co-deletion[17] Both XIAP and cIAP1/2 have been reported to ubiquitylate RIPK2 to promote anti-microbial cytokine responses following NOD receptor ligation[18,19]. It was recently reported that LPS stimulation of caspase-8-deficient dendritic cells induces RIPK3-dependent activation of NLRP3, triggering IL-1b-dependent endotoxic shock in vivo[25]. Despite these advances, it remains unclear how IAPs repress LPS-induced. RIPK3 can drive inflammation in the absence of necroptotic cell death
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