Inhibitor of apoptosis (IAP) proteins ubiquitylate RIP3 kinase and repress apoptosis, necroptosis, NLRP3 inflammasome activation and systemic inflammation

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 IAP..