The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation

RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation. [Display omitted] •ZBP1 and TRIF induce necroptosis-mediated perinatal death in Ripk1R588E/R588E mice•TRADD induces inflammation and early postnatal death in Ripk1R588E/R588EMlkl−/−•RIPK3 causes MLKL-independent postnatal inflammation in Ripk1R588E/R588E mice•The RIPK1 DD determines how ZBP1 and TRIF engage and activate RIPK3 RIPK1 regulates cell death via kinase-dependent and kinase-independent mechanisms. Utilizing mice expressing RIPK1 with a point mutation disrupting its death domain, Imai et al. show that RIPK1 death domain interactions are critical to suppress ZBP1- and TRIF-induced activation of RIPK3 and necroptosis.