| Summary: | Summary: Cellular inhibitor of apoptosis proteins cIAP1 and cIAP2 ubiquitinate nuclear factor κB (NF-κB)-inducing kinase (NIK) to suppress non-canonical NF-κB signaling and substrates such as receptor interacting protein kinase 1 (RIPK1) to promote cell survival. We investigate how these functions contribute to homeostasis by eliminating cIap2 from adult cIap1-deficient mice. cIAP1 and cIAP2 (cIAP1/2) deficiency causes rapid weight loss and inflammation, with aberrant cell death, indicated by cleaved caspases-3 and -8, prevalent in intestine and liver. Deletion of Casp8 and Ripk3 prevents this aberrant cell death, reduces the inflammation, and prolongs mouse survival, whereas Ripk3 loss alone offers little benefit. Residual inflammation in mice lacking cIap1/2, Casp8, and Ripk3 is reduced by inhibition of NIK. Loss of Casp8 and Mlkl (mixed lineage kinase domain-like), but not Mlkl loss alone, also prevents cIAP1/2-deficient mice from dying around embryonic day 11. Therefore, a major function of cIAP1/2 in vivo is to suppress caspase-8-dependent cell death. : Zhang et al. use mouse genetics to show that the ubiquitin ligases cIAP1 and cIAP2 are critical for suppressing pro-inflammatory caspase-8-dependent cell death. Loss of caspase-8 (in combination with RIPK3 or MLKL loss) prevents embryonic lethality due to cIAP1/2 deficiency and ameliorates inflammation when cIAP1/2 are deleted from adult mice. Keywords: cIAP1, cIAP2, apoptosis, caspase-8, NIK
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