Abstract
IAP proteins limit RIPK3-dependent cell death, and caspase-8 and NLRP3-caspase-1 inflammasome activation of IL-1β, yet the mechanisms remain unclear. We report that IAPs (cIAP1/cIAP2/XIAP) induce RIPK3 ubiquitylation following LPS stimulation. Upon IAP loss, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, RIPK3 kinase and MLKL were essential for LPS-induced NLRP3 activation in the absence of both IAPs and caspase-8. Both XIAP and RIPK1 expression were necessary to limit LPS-induced RIPK3 activity. Notably, IL-1 dependent autoantibody-mediated arthritis was exacerbated in mice lacking IAPs, and was reduced by deletion of RIPK3, but not MLKL. These results reveal unique mechanisms for IAPs in repressing RIPK3 inflammatory signalling and cell death.
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