IAPs limit activation of RIP kinases by TNF receptor 1 during development

Inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP (X‐linked IAP) regulate apoptosis and cytokine receptor signalling, but their overlapping functions make it difficult to distinguish their individual roles. To do so, we deleted the genes for IAPs separately and in combination. While lack of any one of the IAPs produced no overt phenotype in mice, deletion of cIap1 with cIap2 or Xiap resulted in mid‐embryonic lethality. In contrast, Xiap −/− cIap2 −/− mice were viable. The death of cIap2 −/− cIap1 −/− double mutants was rescued to birth by deletion of tumour necrosis factor ( TNF ) receptor 1 , but not TNFR2 genes. Remarkably, hemizygosity for receptor‐interacting protein kinase 1 ( Ripk1 ) allowed Xiap −/− cIap1 −/− double mutants to survive past birth, and prolonged cIap2 −/− cIap1 −/− embryonic survival. Similarly, deletion of Ripk3 was able to rescue the mid‐gestation defect of cIap2 −/− cIap1 −/− embryos, as these embryos survived to E15.5. cIAPs are therefore required during development to limit activity of RIP kinases in the TNF receptor 1 signalling pathway. The inhibitor of apoptosis proteins cIAP1, cIAP2, and XIAP exert overlapping functions in apoptosis and cytokine signalling. A series of single‐ and double‐knockout mice reveal an essential function of IAP proteins in preventing TNF receptor 1‐induced, RIP kinase 1‐ and 3‐dependent cell death during embryogenesis.