The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammationopen access
- Authors
- Imai, Takashi; Lin, Juan; Kaya, Göksu Gökberk; Ju, Eunjin; Kondylis, Vangelis; Kelepouras, Konstantinos; Liccardi, Gianmaria; Kim, Chun; Pasparakis, Manolis
- Issue Date
- May-2024
- Publisher
- Cell Press
- Keywords
- apoptosis; caspase-8; FADD; inflammation; necroptosis; RIPK1; TNFR1; TRADD; TRIF; ZBP1
- Citation
- Immunity, pp 1 - 24
- Pages
- 24
- Indexed
- SCIE
SCOPUS
- Journal Title
- Immunity
- Start Page
- 1
- End Page
- 24
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/119297
- DOI
- 10.1016/j.immuni.2024.04.016
- ISSN
- 1074-7613
1097-4180
- 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 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. © 2024 The Author(s)
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