The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation.
Immunity
; 57(7): 1497-1513.e6, 2024 Jul 09.
Article
em En
| MEDLINE
| ID: mdl-38744293
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas de Ligação a RNA
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Proteínas Adaptadoras de Transporte Vesicular
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Proteína Serina-Treonina Quinases de Interação com Receptores
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Necroptose
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Inflamação
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article