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一种可行的非激酶活性RIPK3 D143N小鼠模型揭示了它在驱动TNF诱导的炎症性疾病中的支架功能

Yayun Du¹, Jingjing Li¹, Cong Zhao¹

¹State Key Laboratory of Common Mechanism Research for Major Diseases, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.

Cell death discovery

|February 23, 2026

概括

一个新的RIPK3酶死亡的小鼠模型揭示了RIPK3.

科学领域:

细胞生物学细胞生物学
免疫学免疫学免疫学
遗传学是一个遗传学.

背景情况:

受体相互作用蛋白激酶3 (RIPK3) 调节亡,一种编程细胞死亡的形式.
在疾病中,RIPK3的基因酶依赖和基因酶独立功能的不同作用尚未完全理解.
现有的酶不活性RIPK3模型表现出胚胎致死性,限制了它们的实用性.

研究的目的:

为了生成和描述一种新的,可行的酶不活性RIPK3小鼠模型 (Ripk3^{D143N/D143N).}
在细胞死亡和炎症性疾病中剖析RIPK3的酶依赖和酶独立功能.
探索准RIPK3的支架功能治疗潜力.

主要方法:

基因酶死亡的Ripk3^D143N/D143N敲进小鼠的生成和表征.
评估通过各种刺激诱导亡的情况.
在caspase-8缺乏的小鼠中对胚胎致死性救援的评估.
对TNF驱动的炎症性疾病保护的分析.
研究RIPK3在JAK-STAT1信号通路激活中的作用.
药理上抑制JAK1/2以评估疾病的致病性.

主要成果:

Ripk3^D143N/D143N小鼠是可行的和肥沃的,表明RIPK3激酶活性是不可或缺的发展.
在Caspase-8缺乏的小鼠中,D143N突变阻止了亡并挽救了胚胎死亡.
与RIPK3缺乏的小鼠相比,Ripk3^D143N/D143N小鼠对炎症性疾病的保护降低了,这突显了酶独立的作用.
RIPK3的支架功能通过JAK-STAT1激活促进炎症和组织损伤.
在这个模型中,JAK1/2抑制有效地减少了疾病的发病.

结论:

里普克3^D143N/D143N鼠标是区分RIPK3的激酶和支架功能的一个有价值的模型.
RIPK3具有关键的酶独立支架功能,可以驱动炎症和组织损伤.
针对RIPK3的支架功能,可能通过JAK-STAT1抑制,为炎症性疾病提供治疗策略.

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