德国科隆大学Manolis Pasparakis、Juan Lin研究组的最新研究发现，RIPK1死亡结构域抑制ZBP1和TRIF介导的细胞死亡和炎症反应。2024年5月13日，国际学术期刊《免疫》发表了这一成果。

据悉，RIPK1 是一种调节细胞死亡和炎症的多功能激酶，与炎症性疾病的发病机制有关。RIPK1以激酶依赖和非依赖的方式促进或抑制细胞凋亡和坏死，但其潜在机制仍不甚明了。

研究人员发现破坏 RIPK1死亡结构域（DD）的突变（R588E），会导致ZBP1介导的坏死诱导性围产期死亡。

此外，这些小鼠在出生后会发生炎症病理变化，这种病理变化是不依赖于坏死蛋白酶TNFR1、TRADD和TRIF信号，部分需要RIPK3。生化机理研究发现，在野生型细胞中，ZBP1和TRIF介导的RIPK3激活需要RIPK1激酶活性，而在Ripk1^R588E/R588E 细胞中则不需要，这表明其依赖于RIPK1 DD的寡聚化，其与FADD的相互作用决定了ZBP1和TRIF激活RIPK3的机制。

总之，这些发现揭示了依赖于RIPK1 DD信号传导的关键生理作用，它对调节组织稳态和炎症都非常重要。

附：英文原文

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

Author: Takashi Imai, Juan Lin, Gksu Gkberk Kaya, Eunjin Ju, Vangelis Kondylis, Konstantinos Kelepouras, Gianmaria Liccardi, Chun Kim, Manolis Pasparakis

Issue&Volume: 2024-05-13

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.

DOI: 10.1016/j.immuni.2024.04.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00221-8