The RIPK1 death domain restrains ZBP1- and TRIF- mediated cell death and inflammation
Abstract
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 under-
stood. 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.
Read more at Immunity 57, 1–17